Tamper-resistant oral opioid agonist formulations

ABSTRACT

Disclosed is an oral dosage form comprising (i) an opioid agonist in releasable form and (ii) a sequestered opioid antagonist which is substantially not released when the dosage form is administered intact.

This application claims benefit of U.S. Provisional No. 60/181,369 filedFeb. 8, 2000, the disclosure of which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Opioids, also known as opioid agonists, are a group of drugs thatexhibit opium or morphine-like properties. The opioids are employedprimarily as moderate to strong analgesics, but have many otherpharmacological effects as well, including drowsiness, respiratorydepression, changes in mood and mental clouding without a resulting lossof consciousness. Opioids act as agonists, interacting withstereospecific and saturable binding sites in the brain and othertissues. Endogenous opioid-like peptides are present particularly inareas of the central nervous system that are presumed to be related tothe perception of pain; to movement, mood and behavior, and to theregulation of neuroendocrinological functions. Opium contains more thantwenty distinct alkaloids. Morphine, codeine and papaverine are includedin this group.

By the middle of the nineteenth century, the use of pure alkaloids suchas morphine rather than crude opium preparations began to spreadthroughout the medical world. Parenteral use of morphine tended toproduce a more severe variety of compulsive drug use than crude opiumpreparations. The problem of addiction to opioids stimulated a searchfor potent analgesics that would be free of the potential to produceaddiction. By 1967, researchers had concluded that the complexinteractions among morphine-like drugs, antagonists, and what was thencalled “mixed agonist-antagonist” could best be explained by postulatingthe existence of more than one type of receptor for opioids and relateddrugs. With the advent of new totally synthetic entities withmorphine-like actions, the term “opioid” was generally retained as ageneric designation for all exogenous substances that bindstereo-specifically to any of several subspecies of opioid receptors andproduce agonist actions. While this greater understanding advanced thescience of pharmacology, it did not result in the development of ananalgesic opioid free of abuse potential.

The potential for the development of tolerance and physical dependencewith repeated opioid use is a characteristic feature of all the opioiddrugs, and the possibility of developing psychological dependence (i.e.,addiction) is one of the major concerns in the use of the treatment ofpain with opioids, even though iatrogenic addiction is rare. Anothermajor concern associated with the use of opioids is the diversion ofthese drugs from the patient in pain to another (non-patient) forillicit purposes, e.g., to an addict.

The overall abuse potential of an opioid is not established by any onesingle factor. Instead, there is a composite of factors, including, thecapacity of the drug to produce the kind of physical dependence in whichdrug withdrawal causes sufficient distress to bring about drug-seekingbehavior; the ability to suppress withdrawal symptoms caused bywithdrawal from other agents; the degree to which it induces euphoriasimilar to that produced by morphine and other opioids; the patterns oftoxicity that occur when the drug is dosed above its normal therapeuticrange; and physical characteristics of the drugs such as watersolubility. Such physical characteristics may determine whether the drugis likely to be abused by the parenteral route.

In the United States, the effort to control the compulsive drug userincludes efforts to control drug availability by placing restrictions onthe use of opioids in the treatment of pain of compulsive drug users. Inpractice, the physician is often faced with a choice of administeringpotent opioid analgesics even to persons who seem predisposed to developpsychological dependence, i.e., addiction, on such drugs. In view ofthis problem, it has been recommended that these patients should not begiven an opioid when another drug without a potential for abuse willsuffice; and further that these patients should not be provided with adosage form which may be parenterally abused and should only be given afew days' supply at any one time.

At least three basic patterns of opioid use and dependence have beenidentified. The first involves individuals whose drug use begins in thecontext of medical treatment and who obtain their initial suppliesthrough legitimate sources, e.g., physicians. Another pattern beginswith experimental or “recreational” drug use and progresses to moreintensive use. A third pattern involves users who begin in one oranother of the preceding patterns, but later switch to oral opioids suchas methadone, obtained from licensed addiction treatment programs.

Tolerance refers to the need to increase the dose of opioid over aperiod of time in order to achieve the same level of analgesia oreuphoria, or the observation that repeated administration of the samedose results in decreased analgesia, euphoria, or other opioid effects.It has been found that a remarkable degree of tolerance develops to therespiratory depressant, analgesic, sedative, emetic and euphorigeniceffects of opioids. However, the rate at which this tolerance maydevelop in either an addict or in a patient requiring treatment of paindepends on the pattern of use. If the opioid is used frequently, it maybe necessary to increase the dose. Tolerance does not develop equally orat the same rate to all the effects of opioids, and even users who arehighly tolerant to respiratory depressant effects continue to exhibitmeiosis and constipation. Tolerance to opioids largely disappears whenthe withdrawal syndrome has been completed.

Physical dependence may develop upon repeated administrations orextended use of opioids. Physical dependence is gradually manifestedafter stopping opioid use or is precipitously manifested (e.g., within afew minutes) after administration of a narcotic antagonist (referred to“precipitated withdrawal”). Depending upon the drug to which dependencehas been established and the duration of use and dose, symptoms ofwithdrawal vary in number and kind, duration and severity. The mostcommon symptoms of the withdrawal syndrome include anorexia, weightloss, pupillary dilation, chills alternating with excessive sweating,abdominal cramps, nausea, vomiting, muscle spasms, hyperirritability,lacrimation, rhinorrhea, goose flesh and increased heart rate. Naturalabstinence syndromes typically begin to occur 24-48 hours after the lastdose, reach maximum intensity about the third day and may not begin todecrease until the third week. Precipitated abstinence syndromesproduced by administration of an opioid antagonist vary in intensity andduration with the dose and the specific antagonist, but generally varyfrom a few minutes to several hours in length.

Psychological dependence (i.e., addiction) on opioids is characterizedby drug-seeking behavior directed toward achieving euphoria and escapefrom, e.g., psychosocioeconomic pressures. An addict will continue toadminister opioids for non-medicinal purposes and in the face ofself-harm.

There have previously been attempts in the art to control the abusepotential associated with opioid analgesics. For example, thecombination of pentazocine and naloxone has been utilized in tabletsavailable in the United States, commercially available as Talwin®Nx fromSanofi-Winthrop. Talwin®Nx contains pentazocine hydrochloride equivalentto 50 mg base and naloxone hydrochloride equivalent to 0.5 mg base.Talwin®Nx is indicated for the relief of moderate to severe pain. Theamount of naloxone present in this combination has low activity whentaken orally, and minimally interferes with the pharmacologic action ofpentazocine. However, this amount of naloxone given parenterally hasprofound antagonistic action to narcotic analgesics. Thus, the inclusionof naloxone is intended to curb a form of misuse of oral pentazocinewhich occurs when the dosage form is solubilized and injected.Therefore, this dosage has lower potential for parenteral misuse thanprevious oral pentazocine formulations. However, it is still subject topatient misuse and abuse by the oral route, for example, by the patienttaking multiple doses at once. A fixed combination therapy comprisingtilidine (50 mg) and naloxone (4 mg) has been available in Germany forthe management of severe pain since 1978 (Valoron®N, Goedecke). Therationale for the combination of these drugs is effective pain reliefand the prevention of tilidine addiction through naloxone-inducedantagonisms at the morphine receptor. A fixed combination ofbuprenorphine and naloxone was introduced in 1991 in New Zealand(Temgesic®Nx, Reckitt & Colman) for the treatment of pain.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the invention to provide an oral dosage form of anopioid agonist that is useful for decreasing the potential for abuse ofthe opioid agonist contained therein.

It is an object of a preferred embodiment of the invention to provide anoral dosage form of an opioid agonist that is useful for decreasing thepotential abuse of the opioid agonist without affecting the analgesiceffects of the opioid agonist or incurring the risk of precipitatingwithdrawal.

It is an object of a preferred embodiment of the invention to provide anoral dosage form of an opioid agonist that is resistant to misuse, abuseor diversion, wherein said resistance does not depend on individualpatient-specific differences in the effects of co-administered opioidagonist and antagonist mixtures.

It is an object of a preferred embodiment of the invention to provide anoral dosage form containing an effective dose of an opioid agonist alongwith a dose of opioid antagonist which does not change the analgesicefficacy of the opioid agonist when the dosage form is orallyadministered intact, but which can prevent abuse if the dosage form istampered with by interfering with the effect of the opioid agonist.

It is an object of a preferred embodiment of the invention to provide amethod for preventing abuse of an oral opioid dosage form where thedosage form also includes a dose of opioid antagonist which issequestered, e.g., is not bioavailable when the dose is administeredintact but is bioavailable when the dosage form is tampered with (e.g.,in an attempt to misuse the dose of opioid analgesic).

It is a further object of a preferred embodiment of the invention toprovide oral dosage forms that are intended for or are suitable for usein the management of acute or chronic pain where alteration of theopioid agonist's analgesic affects must be avoided such as in cases oftolerance, physical dependence or individual variability in hepaticmetabolism or physiology.

It is a further object of a preferred embodiment of the invention toprovide a method of treating pain in human patients with an oral dosageform of an opioid agonist while reducing its misuse by oral, parenteral,intranasal and/or sublingual route.

Some or all of the above objects and others are achieved by embodimentsof the present invention, which is directed in part to an oral dosageform comprising an opioid agonist and an opioid antagonist, wherein theopioid antagonist is present in a substantially non-releasable form(i.e., “sequestered”). In preferred embodiments, the dosage formcontains an orally therapeutically effective amount of the opioidagonist, the dosage form providing a desired analgesic effect. Becausethe opioid antagonist is present in a substantially non-releasable form,it does not substantially block the analgesic effect of the opioidagonist when the dosage form is orally administered intact, and does notpose a risk of precipitation of withdrawal in opioid tolerant ordependent patients.

In preferred embodiments, the oral dosage form of the present inventionis directed to an oral dosage form comprising (i) an opioid agonist inreleasable form and (ii) a sequestered opioid antagonist which issubstantially not released when the dosage form is administered intact,such that the ratio of the amount of antagonist released from the dosageform after tampering to the amount of the antagonist released from theintact dosage form is about 4:1 or greater, based on the in-vitrodissolution at 1 hour of the dosage form in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C.wherein the agonist and antagonist are interdispersed and are notisolated from each other in two distinct layers.

In other embodiments, the invention is directed to an oral dosage formcomprising (i) an opioid agonist in releasable form and (ii) asequestered opioid antagonist which is substantially not released whenthe dosage form is administered intact, such that the ratio of theamount of antagonist released from the dosage form after tampering tothe amount of the antagonist released from the intact dosage form isabout 4:1 or greater, based on the in-vitro dissolution at 1 hour of thedosage form in 900 ml of Simulated Gastric Fluid using a USP Type II(paddle) apparatus at 75 rpm at 37 degrees C. wherein the antagonist isin the form of multiparticulates individually coated with a sequesteringmaterial which substantially prevents release of the antagonist.

In other embodiments, the invention is directed to an oral dosage formcomprising (i) an opioid agonist in releasable form and (ii) asequestered opioid antagonist which is substantially not released whenthe dosage form is administered intact, such that the ratio of theamount of antagonist released from the dosage form after tampering tothe amount of the antagonist released from the intact dosage form isabout 4:1 or greater, based on the in-vitro dissolution at 1 hour of thedosage form in 900 ml of Simulated Gastric Fluid using a USP Type II(paddle) apparatus at 75 rpm at 37 degrees C. wherein the antagonist isdispersed in a matrix comprising a sequestering material whichsubstantially prevents the release of the antagonist.

In other embodiments, the invention is directed to an oral dosage formcomprising (i) an opioid agonist in releasable form and (ii) asequestered opioid antagonist which is substantially not released whenthe dosage form is administered intact, such that the ratio of theamount of antagonist contained in the intact dosage form to the amountof the antagonist released from the intact dosage form after 1 hour isabout 4:1 or greater, based on the in-vitro dissolution at 1 hour of thedosage form in 900 ml of Simulated Gastric Fluid using a USP Type II(paddle) apparatus at 75 rpm at 37 degrees C. wherein the agonist andantagonist are interdispersed and are not isolated from each other intwo distinct layers.

In other embodiments, the invention is directed to an oral dosage formcomprising (i) an opioid agonist in a releasable form; and (ii) asequestered opioid antagonist which is substantially not released whenthe dosage form is administered intact, such that the amount ofantagonist released from the intact dosage form after 1 hour is lessthan an amount bioequivalent to 0.25 mg naltrexone and the amount of theantagonist released after 1 hour from the dosage form after tampering isan amount bioequivalent to 0.25 mg naltrexone or more, the release basedon the dissolution at 1 hour of the dosage form in 900 ml of SimulatedGastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37degrees C., wherein the agonist and antagonist are interdispersed andare not isolated from each other in two distinct layers. Preferably, theamount of antagonist released after 1 hour from the tampered dosage formis an amount bioequivalent to about 0.5 mg naltrexone or more and/or theamount of antagonist released after 1 hour from the intact dosage formis an amount bioequivalent to about 0.125 mg naltrexone or less.

In other embodiments, the invention is directed to an oral dosage formcomprising (i) an opioid agonist in a releasable form; and (ii)sequestered naltrexone or a pharmaceutically acceptable sat thereofwhich is substantially not released when the dosage form is administeredintact, such that the amount of naltrexone released from the intactdosage form after 1 hour is less than 0.25 mg and the amount of thenaltrexone released after 1 hour from the dosage form after tampering is0.25 mg or more, the release based on the dissolution at 1 hour of thedosage form in 900 ml of Simulated Gastric Fluid using a USP Type II(paddle) apparatus at 75 rpm at 37 degrees C., wherein the agonist andnaltrexone are interdispersed and are not isolated from each other intwo distinct layers. Alternatively in this embodiment, the oral theamount of antagonist released after 1 hour from the tampered dosage formis about 0.5 mg naltrexone or more and/or the amount of antagonistreleased after 1 hour from the intact dosage form is about 0.125 mgnaltrexone or less.

In other embodiments, the invention is directed to an oral dosage formcomprising (i) a therapeutic effect of an opioid agonist; and (ii) asequestered opioid antagonist, such that at 1 hour after oraladministration, the intact dosage form releases not more than about 25%of the antagonist, the dosage form providing analgesia and the releasedantagonist not affecting analgesic efficacy, wherein the agonist andantagonist are interdispersed and are not isolated from each other intwo distinct layers. Preferably, the intact dosage form releases notmore than about 12.5% of the antagonist.

In other embodiments, the invention is directed to an oral dosage formcomprising: (i) an opioid agonist in a releasable form; and an (ii)opioid antagonist in substantially non-releasable form wherein theantagonist is in the form of multiparticulates individually coated witha material which substantially prevents release of the antagonist.

In other embodiments, the invention is directed to an oral dosage formcomprising: (i) an opioid agonist in a releasable form; and an (ii)opioid antagonist in substantially non-releasable form wherein theantagonist is dispersed in a matrix comprising a material whichsubstantially prevents the release of the antagonist.

In certain embodiments of the invention, the intact dosage form of thepresent invention releases some of the opioid antagonist containedtherein at 1 hour after oral administration, e.g., the dosage formreleases at least 0.025 mg naltrexone or a bioequivalent dose of anotherantagonist at 1 hour. In these embodiments, the dosage form providesanalgesia to the patient and the released antagonist does not affectanalgesic efficacy. In these embodiments, the dosage form preferablydoes not release 0.25 mg or more naltrexone at 1 hour afteradministration. The release of naltrexone from the intact dosage formmay be measured for purposes of these embodiments, based on the in-vitrodissolution of the dosage form at 1 hour in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C.

In other embodiments, the invention is directed to an oral dosage formcomprising an opioid agonist and naltrexone or a salt thereof in asubstantially non-releasable form; wherein the agonist and naltrexoneare at least partially interdispersed.

In other embodiments, the invention is directed to an oral dosage formcomprising an opioid agonist; and an orally-bioavailable opioidantagonist in a substantially non-releasable form; wherein the agonistand antagonist are at least partially interdispersed.

In embodiments of the invention wherein the antagonist is in the form ofmultiparticulates coated with a sequestering material, themultiparticulates can be in the form of inert beads coated with theantagonist and overcoated with the material, or alternatively in theform of a granulation comprising the antagonist and the material. Themultiparticulates can be dispersed in a matrix comprising the opioidagonist or contained in a capsule with the opioid agonist.

In embodiments of the invention wherein the antagonist is dispersed in amatrix comprising a sequestering material which substantially preventsthe release of the antagonist, the matrix can be in the form of pellets.The pellets can be dispersed in another matrix comprising the opioidagonist or contained in a capsule with the opioid agonist.

In other embodiments of the invention, part of the antagonist is in amatrix and/or part of the antagonist is in a coated bead.

In certain embodiments of the invention which exhibit theabove-disclosed ratio of about 4:1 or greater concerning the amount ofantagonist released from the dosage form after tampering to the amountof said antagonist released from the intact dosage form based on thedissolution at 1 hour of the dosage form in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C.,the intact dosage form releases 22.5% or less of the antagonist after 1hour and the tampered dosage form releases 90% or more antagonist after1 hour. In another embodiment, the intact dosage form releases 20% orless of said antagonist after 1 hour and the tampered dosage formreleases 80% or more antagonist after 1 hour. In another embodiment, theintact dosage form releases 10% or less of said antagonist after 1 hourand the tampered dosage form releases 40% or more antagonist after 1hour. In another embodiment the intact dosage form releases 5% or lessof said antagonist after 1 hour and the tampered dosage form releases20% or more antagonist after 1 hour.

In certain embodiments of the invention, the ratio of the amount ofantagonist released from the dosage form after tampering to the amountof said antagonist released from the intact dosage form based on thedissolution at 1 hour of the dosage form in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C.is 10:1 or greater, 50:1 or greater or 100:1 or greater.

In certain embodiments of the invention, the antagonist is naltrexone ora pharmaceutically acceptable salt thereof. In such embodiments, theintact dosage form preferably releases less than 0.25 mg, preferably0.125 mg or less naltrexone at 1 hour according to the above dissolutionconditions. Preferably, the tampered dosage form releases 0.25 mg ormore naltrexone at 1 hour under the same conditions.

In certain embodiments of the invention, the ratio of the amount ofantagonist released from the dosage form after tampering to the amountof said antagonist released from the intact dosage form based on thedissolution at 1 hour of the dosage form in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37 degrees C.is 10:1 or greater, 50:1 or greater or 100:1 or greater.

In certain embodiments of the dosage form the antagonist in asubstantially non-releasable form is adapted to release less than 15% byweight in vivo after 36 hours. In certain embodiments of the dosage formthe antagonist in a substantially non-releasable form is adapted torelease less than 8% by weight in vivo after 36 hours. In certainembodiments of the dosage form the antagonist in a substantiallynon-releasable form is adapted to release less than 3% by weight in vivoafter 36 hours. In certain embodiments of the dosage form the antagonistin a substantially non-releasable form is adapted to release less than1% by weight in vivo after 36 hours. In certain embodiments of thedosage form the antagonist in a substantially non-releasable form isadapted to release less than 0.5% by weight in vivo after 36 hours.

The invention is also directed to methods of preventing abuse of anopioid agonist utilizing the dosage forms disclosed herein. The methodcan comprise providing the opioid agonist in an oral dosage formtogether with an opioid antagonist, wherein the opioid antagonist ispresent in a form which is in a substantially non-releasable form upondigestion when the integrity of the dosage form is maintained untildigestion begins, but which becomes bioavailable if subjected totampering (e.g., crushing, shear forces which break up the dosage form,etc., solvents or temperatures of greater than 45° C.).

Another embodiment of the invention is directed to a method ofdecreasing the abuse of an opioid agonist in an oral dosage form,comprising preparing an oral dosage form as disclosed herein. Forexample, the method can comprise preparing a dosage form which comprises(i) an orally therapeutically effective amount of an opioid agonist and(ii) an opioid antagonist in a substantially non-releasable form suchthat said dosage form provides a desired analgesic effect and saidantagonist does not substantially block the analgesic effect of theopioid agonist when said dosage form is administered orally intact. Inalternative embodiments, the effect of the opioid agonist is at leastpartially blocked when said dosage form tampered with, e.g., chewed,crushed or dissolved in a solvent, and administered orally,intranasally, parenterally or sublingually.

The invention is also directed to a method of treating pain with thedosage forms disclosed herein. The method can comprise providing an oraldosage form containing an opioid agonist in a releasable form and anopioid antagonist in substantially non-releasable form; and orallyadministering the intact oral dosage form.

Another embodiment of the invention is directed to a method of treatingpain with the disclosed dosage forms. In certain embodiments, the methodof treating pain in patients with a dosage form having less abusepotential comprises providing an oral dosage form containing areleasable form of an opioid agonist and a substantially non-releasableform of an opioid antagonist; and orally administering the oral dosageform to provide a blood plasma level of agonist greater than the minimumanalgesic concentration of the opioid agonist.

The invention is also directed to methods of preparing the dosage formsdisclosed herein. In certain embodiments, the invention comprises amethod of preparing an oral dosage form comprising pretreating an opioidantagonist to render it substantially non-releasable; and combining thepretreated antagonist with a releasable form of an opioid agonist in amanner that maintains the integrity of the non-releasable form of theantagonist.

Certain embodiments of the invention are directed to formulationswherein the agonist and antagonist are interdispersed and are notisolated from each other in two distinct layers. However in certainembodiments, the agonist and antagonist are partially interdispersed

The term “analgesic effectiveness” is defined for purposes of thepresent invention as a satisfactory reduction in or elimination of pain,along with a tolerable level of side effects, as determined by the humanpatient. The phrase “not substantially blocking the analgesic effect ofan opioid agonist” means that the opioid antagonist does not block theeffects of the opioid agonist in sufficient degree as to render thedosage form therapeutically less effective for providing analgesia. Thephrase “risk of precipitation of withdrawal” means that the properaction of the formulation does not depend on a specific ratio of agonistto antagonist or differential metabolism of either.

The term “an opioid antagonist in a substantially non-releasable form”refers to an opioid antagonist that is not released or substantially notreleased at one hour after the intact dosage form containing both opioidagonist and the opioid antagonist is orally administered (i.e., withouthaving been tampered with). For purposes of the invention, the amountreleased after oral administration of the intact dosage form may bemeasured in-vitro via the dissolution at 1 hour of the dosage form in900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatusat 75 rpm at 37 degrees C. Such a dosage form is also referred to ascomprising a “sequestered antagonist”.

Although the preferred embodiments of the invention comprise an opioidantagonist in a form that completely prevents the release of the opioidantagonist, the invention also includes an antagonist in a substantiallynon-releasable form. The term “substantially not released” refers to theantagonist that might be released in a small amount, as long as theamount released is not affect or does not significantly affect analgesicefficacy when the dosage form is orally administered to humans asintended.

In certain preferred embodiments of the invention, the substantiallynon-releasable form of the antagonist is resistant to laxatives (e.g.,mineral oil) used to manage delayed colonic transit and to achlorhydricstates.

In certain embodiments, the substantially non-releasable form of anopioid antagonist comprises an opioid antagonist that is formulated withone or more of pharmaceutically acceptable hydrophobic material, suchthat the antagonist is not released or substantially not released duringits transit through the gastrointestinal tract when administered orallyas intended, without having been tampered with.

In certain embodiments of the present invention, the substantiallynon-releasable form of the opioid antagonist is vulnerable tomechanical, thermal and/or chemical tampering, e.g., tampering by meansof crushing, shearing, grinding, chewing and/or dissolution in a solventin combination with heating (e.g., greater than about 45° C.) of theoral dosage form. When thus tampered with, the integrity of thesubstantially non-releasable form of the opioid antagonist will becompromised, and the opioid antagonist will be made available to bereleased. In certain embodiments, when the dosage form is chewed,crushed or dissolved and heated in a solvent, and administered orally,intranasally, parenterally or sublingually, the analgesic or euphoriceffect of the opioid is reduced or eliminated. In certain embodiments,the effect of the opioid agonist is at least partially blocked by theopioid antagonist. In certain other embodiments, the effect of theopioid agonist is substantially blocked by the opioid antagonist.

The term “tampering” means any manipulation by mechanical, thermaland/or chemical means which changes the physical properties of thedosage form, e.g., to liberate the opioid agonist for immediate releaseif it is in sustained release form, or to make the opioid agonistavailable for inappropriate use such as administration by an alternateroute, e.g., parenterally. The tampering can be, e.g., by means ofcrushing, shearing, grinding, chewing, dissolution in a solvent, heating(e.g., greater than about 45° C.), or any combination thereof.

The term “at least partially blocking the opioid effect,” is defined forpurposes of the present invention to mean that the opioid antagonist atleast significantly blocks the euphoric effect of the opioid agonist,thereby reducing the potential for abuse of the opioid agonist in thedosage form.

In certain preferred embodiments of the present invention, thesubstantially non-releasable form of the opioid antagonist comprisesopioid antagonist particles in a coating that substantially prevents therelease of the antagonist. In preferred embodiments, the coatingcomprising one or more of pharmaceutically acceptable hydrophobicmaterial. The coating is preferably impermeable to the opioid antagonistcontained therein and is insoluble in the gastrointestinal system, thussubstantially preventing the release of the opioid antagonist when thedosage form is administered orally as intended.

Accordingly, when the oral dosage form is not tampered with as tocompromise the integrity of the coating, the opioid antagonist containedtherein will not be substantially released during its first hour oftransit through the gastrointestinal system, and thus would not beavailable for absorption. In certain preferred embodiments of thepresent invention, the hydrophobic material comprises a cellulosepolymer or an acrylic polymer that is insoluble in the gastrointestinalfluids and impermeable to the opioid antagonist.

The term “particles” of opioid antagonist, as used herein, refers togranules, spheroids, beads or pellets comprising the opioid antagonist.In certain preferred embodiments, the opioid antagonist particles areabout 0.2 to about 2 mm in diameter, more preferably about 0.5 to about2 mm in diameter.

In certain embodiments of the present invention, the oral dosage formfurther comprises an opioid antagonist in a releasable form and is thuscapable of being released from the oral dosage form when orallyadministered, the ratio of the opioid agonist to the releasable form ofthe opioid antagonist being such that the dosage form, when administeredorally, is analgesically effective. For example, when the opioidantagonist is coated with a coating that substantially prevents itsrelease, and is then mixed with an opioid agonist and compressed intotablets, certain amounts of the coating might be cracked, thus exposingthe opioid antagonist to be released upon oral administration.

Preferably, the opioid agonist useful for the present invention may beselected from the group consisting of morphine, hydromorphone,hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone andmixtures thereof. Preferred examples of the opioid antagonist useful forthe present invention includes naltrexone, naloxone, nalmefene,cyclazocine, levallorphan, pharmaceutically acceptable salts thereof andmixtures thereof.

In certain embodiments of the present invention, the ratio of the opioidagonist and the opioid antagonist, present in a substantiallynon-releasable form, is about 1:1 to about 50:1 by weight, preferablyabout 1:1 to about 20:1 by weight or 15:1 to about 30:1. The weightratio of the opioid agonist to opioid antagonist, as used in thisapplication, refers to the weight of the active ingredients. Thus, forexample, the weight of the opioid antagonist excludes the weight of thecoating or matrix that renders the opioid antagonist substantiallynon-releasable, or other possible excipients associated with theantagonist particles. In certain preferred embodiments, the ratio isabout 1:1 to about 10:1 by weight. Since the opioid antagonist is in asubstantially non-releasable from, the amount of such antagonist withinthe dosage form may be varied more widely than the opioidagonist/antagonist combination dosage forms where both are available forrelease upon administration as the formulation does not depend ondifferential metabolism or hepatic clearance for proper functioning. Forsafety reasons, the amount of the opioid antagonist present in asubstantially non-releasable form is selected as not to be harmful tohumans even if fully released by tampering with the dosage form.

In certain preferred embodiments of the present invention, the opioidagonist comprises hydrocodone, oxycodone or pharmaceutically acceptablesalts thereof and the opioid antagonist, present in a substantiallynon-releasable form, comprises naloxone, naltrexone or pharmaceuticallyacceptable salts thereof.

The oral dosage form containing an opioid agonist in combination with asubstantially non-releasable form of an opioid antagonist includes, butare not limited to, tablets or capsules. The dosage forms of the presentinvention may include any desired pharmaceutical excipients known tothose skilled in the art. The oral dosage forms may further provide animmediate release of the opioid agonist. In certain embodiments, theoral dosage forms of the present invention provide a sustained releaseof the opioid agonist contained therein. Oral dosage forms providingsustained release of the opioid agonist may be prepared in accordancewith formulations/methods of manufacture known to those skilled in theart of pharmaceutical formulation, e.g., via the incorporation of asustained release carrier into a matrix containing the substantiallynon-releasable form of an opioid antagonist; or via a sustained releasecoating of a matrix containing the opioid agonist and the substantiallynon-releasable form of the opioid antagonist.

The benefits of the abuse-resistant dosage form are especially great inconnection with oral dosage forms of strong opioid agonists (e.g.,oxycodone or hydrocodone), which provide valuable analgesics but areprone to being abused. This is particularly true for sustained releaseopioid agonist products which have a large dose of a desirable opioidagonist intended to be released over a period of time in each dosageunit. Drug abusers take such sustained-release product and crush, grind,extract or otherwise damage the product so that the full contents of thedosage form become available for immediate absorption. Since suchtampering of the dosage form of the invention results in the opioidantagonist also becoming available for absorption, the present inventionprovides a means for frustrating such abuse. In addition, the presentinvention addresses the risk of overdose to ordinary patients from“dumping” effect of the full dose of the opioid agonist if the productis accidentally chewed or crushed.

The term “sustained release” is defined for purposes of the presentinvention as the release of the opioid agonist from the oral dosage format such a rate that blood (e.g., plasma) concentrations (levels) aremaintained within the therapeutic range (above the minimum effectiveanalgesic concentration or “MEAC”) but below toxic levels over a periodof 8 to 24 hours, preferable over a period of time indicative of atwice-a-day or a once-a-day formulation.

The invention may provide for a safer product (e.g., less respiratorydepression), if the product is misused, as well as one with less risk ofabuse.

In certain embodiments, a combination of two opioid agonists is includedin the formulation. In further embodiments, one or more opioid agonistis included and a further non-opioid drug is also included. Suchnon-opioid drugs would preferably provide additional analgesia, andinclude, for example, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs (“NSAIDS”), NMDA antagonists, andcyclooxygenase-II inhibitors (“COX-II inhibitors”).

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, or antihistamine drugs, and the like.

For purposes of the present invention, the term “opioid agonist” isinterchangeable with the term “opioid” or “opioid analgesic” and shallinclude combinations of more than one opioid agonist, and also includethe base of the opioid, mixed agonist-antagonists, partial agonists,pharmaceutically acceptable salts thereof, stereoisomers thereof, ethersand esters thereof, and mixtures thereof.

For purposes of the present invention, the term “opioid antagonist”shall include combinations of more than one opioid antagonist, and alsoinclude the base, pharmaceutically acceptable salts thereof,stereoisomers thereof, ethers and esters thereof, and mixtures thereof.

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed opioidagonists and antagonists. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,secium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparaginate, glutamate and the like.

Some of the opioid agonists and antagonists disclosed herein may containone or more asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms. The present invention isalso meant to encompass all such possible forms as well as their racemicand resolved forms and mixtures thereof. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended to includeboth E and Z geometric isomers. All tautomers are intended to beencompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms is space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposable on its minor image and hence optically active whereinthe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The present invention is further directed to a method of decreasing thepotential for abuse of an opioid agonist in an oral dosage form. Themethod comprises providing the opioid agonist in an oral dosage form asdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the results of Example 20.

FIG. 2 is a graphical representation of the results of Example 23.

FIG. 3 is a graphical representation of the results of Example 24.

DETAILED DESCRIPTION OF THE INVENTION

It has been postulated that there exists at least three subspecies ofopioid receptors, designated mu, kappa, and delta. Within thisframework, the mu receptor is considered to be involved in theproduction of superspinal analgesia, respiratory depression, euphoria,and physical dependence. The kappa receptor is considered to be involvedin inducing spinal analgesia, meiosis and sedation. Activation of thegamma receptors causes dysphoria and hallucinations, as well asrespiratory and vasomotor stimulatory effects. A receptor distinct fromthe mu receptor and designated gamma has been described in the mouse vasdeferens, Lord, et al. Nature, 1977, 267, 495-99. Opioid agonists arethought to exert their agonist actions primarily at the mu receptor andto a lesser degree at the kappa receptor. There are a few drugs thatappear to act as partial agonists at one receptor type or another. Suchdrugs exhibit a ceiling effect. Such drugs include nalorphine, propiram,and buprenorphine. Still other drugs act as competitive antagonists atthe mu receptor and block the effects of morphine-like drugs, byexerting their actions at the kappa and omega receptors. The termagonist-antagonist has evolved to describe such mechanism of actions.

The present invention is directed to a controlled release opioidanalgesic, similar in analgesic spectrum to existing controlled-releaseopioid analgesics, which is formulated in order to reduce and minimizemisuse, abuse and diversion. In certain embodiments, thesecharacteristics are conferred by the inclusion of an opioid antagonistsuch as naltrexone HCl, which is itself formulated in a uniquecontrolled release matrix. The properties of this formulation aredeveloped to liberate the antagonist in conditions of misuse ortampering yet a negligible amount of antagonist would be released (anamount which does not affect the analgesia experienced by the patient)under the prescribed conditions of use.

In certain embodiments of the invention, the release for the antagonistcomponent of the formulation is expressed in terms of a ratio of therelease achieved after tampering, e.g., by crushing or chewing, relativeto the amount released from the intact formulation. The ratio istherefore expressed as [Crushed]/[Whole], and it is desired that thisratio have a numerical range of at least 4:1 or greater (crushed releasein 1 hour/intact release in 1 hour). When the antagonist is naltrexone,it is preferable that the intact dosage form releases less than 0.25 mg,preferably 0.125 mg or less within 1 hour, with 0.25 mg or greaternaltrexone released after 1 hour when the dosage form is crushed orchewed. The derivation of these values are described in Example 17, 18and 19.

The present invention provides an oral dosage form of opioid agonistuseful for decreasing the potential for abuse of the opioid agonistcontained therein. The present invention includes an oral dosage formcomprising an orally therapeutically effective amount of an opioidagonist in combination with an opioid antagonist. The opioid antagonistis present in a substantially non-releasable form.

In certain preferred embodiments, the opioid antagonist in asubstantially non-releasable form comprises opioid antagonist particlescoated with a coating that substantially prevents its release. Inpreferred embodiments, such coating surrounds the antagonist particlesand is impermeable to the drug and is insoluble in the gastrointestinalsystem. When the dosage form of the present invention is orallyadministered to humans, the opioid antagonist is not substantiallyreleased from the coating and is, therefore, not available forabsorption into the body. Thus, the opioid antagonist, although presentin the dosage form, does not substantially block the analgesiceffectiveness of the opioid agonist. However, if the oral dosage form ofthe present invention is tampered with as to compromise the integrity ofthe coating, the opioid antagonist contained therein would be madeavailable to at least partially block the effect of the opioid agonist.This characteristic decreases the potential for abuse or diversion ofthe opioid agonist in the oral dosage form. For example, if one attemptsto abuse the drug contained in the oral dosage form of the presentinvention by, e.g., chewing, crushing, grinding or dissolving it in asolvent with heat (e.g., greater than about 45° C. to about 50° C.), thecoating will be damaged and will no longer prevent the opioid antagonistfrom being released. Upon administration, the opioid antagonist will bereleased and significantly block the euphoric effect of the opioidagonist.

In certain embodiments of the invention, the ratio of the opioid agonistto the coated opioid antagonist is such that when the oral dosage formis tampered with as to compromise the integrity of the coating thatrenders the opioid antagonist substantially non-releasable, the euphoriceffect of the agonist would be negated by the opioid antagonist whenmisused by a human subject orally, parenterally, intranasally orsublingually. In certain preferred embodiments of the invention, theeuphoric effect of the opioid agonist would be negated by the opioidantagonist when misused parenterally or sublingually.

The present invention also includes an oral dosage form which comprisesa releasable form of an opioid antagonist, along with an opioid agonistand coated opioid antagonist particles, the ratio of the agonist to thenon-coated opioid antagonist being such, when administered orally asintended, the oral dosage form is analgesically effective.

In certain other embodiments of the present invention, the opioidantagonist in a substantially non-releasable form comprises an opioidantagonist dispersed in a matrix that renders the antagonistsubstantially non-releasable, wherein the matrix comprises one or moreof a pharmaceutically acceptable hydrophobic material. The antagonist issubstantially not released from the matrix, thus is not made availableto be absorbed during its transit through the gastrointestinal system.

In certain other embodiments of the present invention, the opioidantagonist in a matrix that renders the antagonist substantiallynon-releasable comprises an opioid antagonist dispersed in amelt-extruded matrix, wherein the matrix comprises one or more of apharmaceutically acceptable hydrophobic material.

In preferred embodiments, opioid agonists useful in the presentinvention include, but are not limited to, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl andderivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, nalbuphine, normorphine, norpinanone, opium,oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone,phenomorphan, phanazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, sulfentanil,tilidine, tramadol, mixtures of any of the foregoing, salts of any ofthe foregoing, and the like. In certain embodiments, the amount of theopioid agonist in the claimed opioid composition may be about 75 ng to750 mg.

In certain preferred embodiments, the opioid agonist is selected fromthe group consisting of hydrocodone, morphine, hydromorphone, oxycodone,codeine, levorphanol, meperidine; methadone, oxymorphone, buprenorphine,fentanyl and derivatives thereof, dipipanone, heroin, tramadol,etorphine, dihydroetorphine, butorphanol, levorphanol, or salts thereofor mixtures thereof. In certain preferred embodiments, the opioidagonist is oxycodone or hydrocodone. Equianalgesic doses of theseopioids, in comparison to a 15 mg dose of hydrocodone, are set forth inTable 1 below:

TABLE 1 Equianalgesic Doses of Opioids Opioid Calculated Dose (mg)Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375Levorphanol 1.8 Meperidine 135.0 Methadone 9.0 Morphine 27.0

Although hydrocodone and oxycodone are effective in the management ofpain, there has been an increase in their abuse by individuals who arepsychologically dependent on opioids or who misuse opioids fornon-therapeutic reasons. Previous experience with other opioids hasdemonstrated a decreased abuse potential when opioids are administeredin combination with a narcotic antagonist especially in patients who areex-addicts. Weinhold L L, et al. Buprenorphine Alone and in Combinationwith Naltrexone in Non-Dependent Humans, Drug and Alcohol Dependence1992; 30:263-274; Mendelson J., et al., Buprenorphine and NaloxoneInteractions in Opiate-Dependent Volunteers, Clin Pharm Ther. 1996;60:105-114; both of which are hereby incorporated by reference. Thesecombinations, however, do not contain the opioid antagonist that is in asubstantially non-releasable form. Rather, the opioid antagonist isreleased in the gastrointestinal system when orally administered and ismade available for absorption, relying on the physiology of the host todifferentially metabolize the agonist and antagonist and negate theagonist effects.

Hydrocodone is a semisynthetic narcotic analgesic and antitussive withmultiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrocodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

Oral hydrocodone is also available in Europe (Belgium, Germany, Greece,Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. Aparenteral formulation is also available in Germany as an antitussiveagent. For use as an analgesic, hydrocodone bitartrate is commerciallyavailable in the United States only as a fixed combination withnon-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) forrelief of moderate or moderately severe pain.

A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab® in theU.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with32 mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of the opioid antagonist particlescoated with a coating that renders the antagonist substantiallynon-releasable.

Oxycodone, chemically known as4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.

Oxycodone is commercially available in the United States, e.g., asOxycontin® from Purdue Pharma L.P. as controlled-release tablets fororal administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodonehydrochloride, and as OxyIR™, also from Purdue Pharma L.P., asimmediate-release capsules containing 5 mg oxycodone hydrochloride. Thepresent invention is contemplated to encompass all such formulations,with the inclusion of an opioid antagonist in a substantiallynon-releasable form.

In preferred embodiments, the opioid antagonist of the present inventionincludes naltrexone, nalmefene, cyclazocine, levallorphan and mixturesthereof. In certain preferred embodiments, the opioid antagonist isnaloxone or naltrexone. In certain embodiments, the amount of the opioidantagonist, present in a substantially non-releasable form, may be about10 ng to 275 mg.

Naloxone is an opioid antagonist which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to completely block the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver such that it has been reported to havesignificantly lower potency than as when parenterally administered. Oraldosage of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours. It has been reported that 25% ofnaloxone administered sublingually is absorbed. Weinberg, et al.,Sublingual Absorption of selected Opioid Analgesics, Clin PharmacolTher. (1988); 44:335-340.

Other opioid antagonists, for example, cyclazocine and naltrexone, bothof which have cyclopropylmethyl substitutions on the nitrogen, retainmuch of their efficacy by the oral route and their durations of actionare much longer, approaching 24 hours after oral doses.

In the treatment of patients previously addicted to opioids, naltrexonehas been used in large oral doses (over 100 mg) to prevent euphorigeniceffects of opioid agonists. Naltrexone has been reported to exert strongpreferential blocking action against mu over delta sites. Naltrexone isknown as a synthetic congener of oxymorphone with no opioid agonistproperties, and differs in structure from oxymorphone by the replacementof the methyl group located on the nitrogen atom of oxymorphone with acyclopropylmethyl group. The hydrochloride salt of naltrexone is solublein water up to about 100 mg/cc. The pharmacological and pharmacokineticproperties of naltrexone have been evaluated in multiple animal andclinical studies. See, e.g., Gonzalez J P, et al. Naltrexone: A reviewof its Pharmacodynamic and Pharmacokinetic Properties, and TherapeuticEfficacy in the Management of Opioid Dependence. Drugs 1988; 35:192-213,hereby incorporated by reference. Following oral administration,naltrexone is rapidly absorbed (within 1 hour) and has an oralbioavailability ranging from 5-40%. Naltrexone's protein binding isapproximately 21% and the volume of distribution following single-doseadministration is 16.1 L/kg.

Naltrexone is commercially available in tablet form (Revia®, DuPont) forthe treatment of alcohol dependence and for the blockade of exogenouslyadministered opioids. See, e.g., Revia (naltrexone hydrochloridetablets). Physician's Desk Reference 51^(st) ed., Montvale, N.J.“Medical Economics” 1997; 51:957-959. A dosage of 50 mg Revia® blocksthe pharmacological effects of 25 mg IV administered heroin for up to 24hours.

It is known that when coadministered with morphine, heroin or otheropioids on a chronic basis, naltrexone blocks the development ofphysical dependence to opioids. It is believed that the method by whichnaltrexone blocks the effects of heroin is by competitively binding atthe opioid receptors. Naltrexone has been used to treat narcoticaddiction by complete blockade of the effects of opioids. It has beenfound that the most successful use of naltrexone for a narcoticaddiction is with narcotic addicts having good prognosis, as part of acomprehensive occupational or rehabilitative program involvingbehavioral control or other compliance enhancing methods. For treatmentof narcotic dependence with naltrexone, it is desirable that the patientbe opioid-free for at least 7-10 days. The initial dosage of naltrexonefor such purposes has typically been about 25 mg, and if no withdrawalsigns occur, the dosage may be increased to 50 mg per day. A dailydosage of 50 mg is considered to produce adequate clinical blockade ofthe actions of parenterally administered opioids. Naltrexone has alsobeen used for the treatment of alcoholism as an adjunct with social andpsychotherapeutic methods.

In certain embodiments of the present invention, ratio of the opioidagonist to the substantially non-releasable form of an opioid antagonistin the oral dosage form is such that the effect of the opioid agonist isat least partially blocked when the dosage form is chewed, crushed ordissolved in a solvent and heated, and administered orally,intranasally, parenterally or sublingually. Since the oral dosage formof the present invention, when administered properly as intended, wouldnot substantially release the opioid antagonist, the amount of suchantagonist may be varied more widely than if the opioid antagonist isavailable to be released into the gastrointestinal system upon oraladministration. For safety reasons, the amount of the antagonist presentin a substantially non-releasable form should not be harmful to humanseven if fully released. The ratio of particular opioid agonist toantagonist can be determined without undue experimentation by oneskilled in the art.

In certain embodiments of the present invention, the ratio of the opioidagonist and the opioid antagonist, present in a substantiallynon-releasable form, is about 1:1 to about 50:1 by weight, preferablyabout 1:1 to about 20:1 by weight. In certain preferred embodiments, theratio is about 1:1 to about 10:1 by weight. In a preferred embodiment ofthe invention, the opioid agonist comprises oxycodone or hydrocodone andis present in the amount of about 15-45 mg and the opioid antagonistcomprises naltrexone and is present in about 0.5-5 mg.

The oral dosage form of the present invention may further include, inaddition to an opioid agonist and antagonist, one or more drugs that mayor may not act synergistically therewith. Thus, in certain embodiments,a combination of two opioid agonists may be included in the dosage form,in addition to the opioid antagonist. For example, the dosage form mayinclude two opioid agonists having different properties, such ashalf-life, solubility, potency, and a combination of any of theforegoing. In yet further embodiments, one or more opioid agonist isincluded and a further non-opioid drug is also included, in addition tothe opioid antagonist. Such non-opioid drugs would preferably provideadditional analgesia, and include, for example, aspirin, acetaminophen;non-steroidal anti-inflammatory drugs (“NSAIDS”), e.g., ibuprofen,ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists,e.g., a morphinan such as dextromethorphan or dextrorphan, or ketamine;cyclooxygenase-II inhibitors (“COX-II inhibitors”); and/or glycinereceptor antagonists.

In certain preferred embodiments of the present invention, the inventionallows for the use of lower doses of the opioid analgesic by virtue ofthe inclusion of an additional non-opioid agonist, such as an NSAID or aCOX-2 inhibitor. By using lower amounts of either or both drugs, theside effects associated with effective pain management in humans arereduced.

Suitable non-steroidal anti-inflammatory agents, including ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen,muroprofen, trioxaprofen, suprofen, alminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam orisoxicam, and the like. Useful dosages of these drugs are well known tothose skilled in the art.

N-methyl-D-aspartate (NMDA) receptor antagonists are well known in theart, and encompass, for example, morphinans such as dextromethorphan ordextrorphan, ketamine, d-methadone or pharmaceutically acceptable saltsthereof. For purposes of the present invention, the term “NMDAantagonist” is also deemed to encompass drugs that block a majorintracellular consequence of NMDA-receptor activation, e.g. aganglioside such as GM₁ or GT_(1b) a phenothiazine such astrifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et. al. patents.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.), hereby incorporated by reference.

COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day are therapeuticallyeffective in combination with an opioid analgesic. Alternatively, about0.25 mg to about 7 g per patient per day of a COX-2 inhibitor isadministered in combination with an opioid analgesic.

In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

Preparation of Opioid Antagonist in a Substantially Non-Releasable Form

In certain embodiments of the present invention, an opioid antagonist ina substantially non-releasable form may be prepared by combining theantagonist with one or more of a pharmaceutically acceptable hydrophobicmaterial. For example, opioid antagonist particles may be coated withcoating that substantially prevents the release of the antagonist, thecoating comprising the hydrophobic materials(s). Another example wouldbe an opioid antagonist that is dispersed in a matrix that renders theantagonist to be substantially non-releasable, the matrix comprising thehydrophobic materials(s). In certain embodiments, the pharmaceuticalacceptable hydrophobic material comprises a cellulose polymer selectedfrom the group consisting of ethylcellulose, cellulose acetate,cellulose propionate (lower, medium or higher molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate and cellulose triacetate. An example of ethylcelluloseis one that has an ethoxy content of 44 to 55%. Ethylcellulose may beused in the form of an alcoholic solution. In certain other embodiments,the hydrophobic material comprises polylactic acid, polyglycolic acid ora co-polymer of the polylactic and polyglycolic acid.

In certain embodiments, the hydrophobic material may comprise acellulose polymer selected from the group consisting of cellulose ether,cellulose ester, cellulose ester ether, and cellulose. The cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than zero and up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups present onthe anhydroglucose unit comprising the cellulose polymer that arereplaced by a substituting group. Representative materials include apolymer selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di, and tricellulose alkanylates,moni, di, and tricellulose aroylates, and mono, di, and tricellulosealkenylates. Exemplary polymers include cellulose acetate having a D.S.and an acetyl content up to 21%; cellulose acetate having an acetylcontent up to 32 to 39.8%; cellulose acetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose acetate having a D.S. of 2 to3 and an acetyl content of 35 to 44.8%.

More specific cellulosic polymers include cellulose propionate having aD.S. of 1.8 and a propyl content of 39.2 to 45 and a hydroxyl content of2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetylcontent of 13 to 15% and a butyryl content of 34 to 39%; celluloseacetate butyrate having an acetyl content of 2 to 29%, a butyryl contentof 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylatehaving a D.S. of 2.9 to 3 such as cellulose triacetate, cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrisuccinate, and cellulose trioctanoate; cellulose diacylates having aD.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate,cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulosesuch as cellulose acetate butyrate, cellulose acetate octanoate butyrateand cellulose acetate propionate.

Additional cellulose polymers useful for preparing an opioid antagonistin a substantially non-releasable form includes acetaldehyde dimethylcellulose acetate, cellulose acetate ethylcarbamate, cellulose acetatemethylcarbamate, and cellulose acetate dimethylaminocellulose acetate.

An acrylic polymer useful for preparation of the opioid antagonist in asubstantially non-releasable form includes, but are not limited to,acrylic resins comprising copolymers synthesized from acrylic andmethacrylic acid esters (e.g., the copolymer of acrylic acid lower alkylester and methacrylic acid lower alkyl ester) containing about 0.02 to0.03 mole of a tri (lower alkyl)ammonium group per mole of the acrylicand methacrylic monomers used. An example of a suitable acrylic resin isa polymer manufactured by Rohm Pharma GmbH and sold under the Eudragit®RS trademark. Eudragit RS30D is preferred. Eudragit® RS is a waterinsoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) andtrimethylammoniumethyl methacrylate chloride (TAM) in which the molarratio of TAM to the remaining components (EA and MM) is 1:40. Acrylicresins such as Eudragit® RS may be used in the form of an aqueoussuspension.

In certain embodiments of the invention, the acrylic polymer may beselected from the group consisting of acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate co-polymers.

When the opioid antagonist in a substantially non-releasable formcomprises opioid antagonist particles coated with a coating that rendersthe antagonist substantially non-releasable, and when a cellulosepolymer or an acrylic polymer is used for preparation of the coatingcomposition, suitable plasticizers, e.g., acetyl triethyl citrate and/oracetyl tributyl citrate may also be admixed with the polymer. Thecoating may also contain additives such as coloring agents, talc and/ormagnesium stearate, which are well known in the coating art.

The coating composition may be applied onto the opioid antagonistparticles by spraying it onto the particles using any suitable sprayequipment known in the part. For example, a Wuster fluidized-bed systemmay be used in which an air jet, injected from underneath, fluidizes thecoated material and effects drying while the insoluble polymer coatingis sprayed on. The thickness of the coating will depend on thecharacteristics of the particular coating composition being used.However, it is well within the ability of one skilled in the art todetermine by routine experimentation the optimum thickness of aparticular coating required for a particular dosage form of the presentinvention.

The pharmaceutically acceptable hydrophobic material useful forpreparing an opioid antagonist in a substantially non-releasable formincludes a biodegradable polymer comprising a poly(lactic/glycolic acid)(“PLGA”), a polylactide, a polyglycolide, a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, polyesters, polydioxanone, polygluconate,polylactic-acid-polyethylene oxide copolymers, poly(hydroxybutyrate),polyphosphoester or mixtures or blends of any of these.

In certain embodiments, biodegradable polymer comprises apoly(lactic/glycolic acid), a copolymer of lactic and glycolic acid,having molecular weight of about 2,000 to about 500,000 daltons. Theratio of lactic acid to glycolic acid is from about 100:0 to about25:75, with the ratio of lactic acid to glycolic acid of 65:35 beingpreferred.

Poly(lactic/glycolic acid) may be prepared by the procedure set forth inU.S. Pat. No. 4,293,539 (Ludwig et al.), the disclosure of which ishereby incorporated by reference in its entirety. In brief, Ludwigprepares the copolymer by condensation of lactic acid and glycolic acidin the presence of a readily removable polymerization catalyst (e.g., astrong acid ion-exchange resin such as Dowex HCR-W2-H). The amount ofcatalyst is not critical to the polymerization, but typically is fromabout 0.01 to about 20 parts by weight relative to the total weight ofcombined lactic acid and glycolic acid. The polymerization reaction maybe conducted without solvents at a temperature from about 10° C. toabout 25° C. for about 48 to about 96 hours, preferably under a reducedpressure to facilitate removal of water and by-products.Poly(lactic/glycolic acid) is then recovered by filtering the moltenreaction mixture in an organic solvent such as dichloromethane oracetone and then filtering to remove the catalyst.

Once the opioid antagonist in a substantially non-releasable form isprepared, it may be combined with an opioid agonist, along withconventional excipients known in the art, to prepare the oral dosageform of the present invention.

In certain preferred embodiments of the invention, the oral dosage formis a capsule or a tablet. When being formulated as a tablet, the opioidantagonist and agonist may be combined with one or more inert, non-toxicpharmaceutical excipients which are suitable for the manufacture oftablets. Such excipients include, for example, an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate.

The oral dosage form of the present invention may be formulated toprovide immediate release of the opioid agonist contained therein. Inother embodiments of the invention, however, the oral dosage formprovides sustained-release of the opioid agonist.

In certain embodiments, the oral dosage forms providing sustainedrelease of the opioid agonist may be prepared by admixing the opioidantagonist in a substantially non-releasable form with the agonist anddesirable pharmaceutical excipients to provide a tablet, and thencoating the tablet with a sustained-release tablet coating.

In certain embodiments of the invention, sustained release opioidagonist tablets may be prepared by admixing the substantiallynon-releasable form of an opioid antagonist with an opioid antagonist ina matrix that provides the tablets with sustained-releasing properties.

Detailed description for preparing sustained-release oral dosage formsaccording to the present invention is set forth below.

Preparation of Controlled Release Dosage Forms Containing an OpioidAgonist and a Substantially On-Releasable Form of an Opioid Antagonist

A combination of the opioid agonist and a substantially non-releasableform of an opioid antagonist may be formulated as a controlled orsustained release oral formulation in any suitable tablet, coated tabletor multiparticulate formulation known to those skilled in the art. Thesustained release dosage form may optionally include a sustained releasecarrier which is incorporated into a matrix along with the opioidagonist and a non-available form of an opioid antagonist, or may beapplied as a sustained release coating.

In embodiments in which the opioid agonist comprises hydrocodone, thesustained release oral dosage forms may include analgesic doses fromabout 8 mg to about 50 mg of hydrocodone per dosage unit. In sustainedrelease oral dosage forms where hydromorphone is the therapeuticallyactive opioid, it is included in an amount from about 2 mg to about 64mg hydromorphone hydrochloride. In another embodiment, the opioidagonist comprises morphine, and the sustained release oral dosage formsof the present invention include from about 2.5 mg to about 800 mgmorphine, by weight. In yet another embodiment, the opioid agonistcomprises oxycodone and the sustained release oral dosage forms includefrom about 2.5 mg to about 800 mg oxycodone. In certain preferredembodiments, the sustained release oral dosage forms include from about20 mg to about 30 mg oxycodone. Controlled release oxycodoneformulations are known in the art. The following documents describevarious controlled release oxycodone formulations suitable for use inthe invention described herein, and processes for their manufacture:U.S. Pat. Nos. 5,266,331; 5,549,912; 5,508,042; and 5,656,295. Theopioid agonist may comprise tramadol and the sustained release oraldosage forms may include from about 25 mg to 800 mg tramadol per dosageunit. The dosage form may contain more than one opioid agonist toprovide a substantially equivalent therapeutic effect. Alternatively,the dosage form may contain molar equivalent amounts of other salts ofthe opioid agonists useful in the present invention.

In one preferred embodiment of the present invention, the sustainedrelease dosage form comprises such particles comprising the opioidagonist, wherein the particles have diameter from about 0.1 mm to about2.5 mm, preferably from about 0.5 mm to about 2 mm.

The opioid agonist particles are preferably film coated with a materialthat permits release of the opioid agonist at a sustained rate in anaqueous medium. The film coat is chosen so as to achieve, in combinationwith the other stated properties, a desired in-vitro release rate. Thesustained release coating formulations of the present invention shouldbe capable of producing a strong, continuous film that is smooth andelegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free.

The dosage forms comprising an opioid agonist and a substantiallynon-releasable opioid antagonist may optionally be coated with one ormore materials suitable for the regulation of the opioid agonist releaseor for the protection of the formulation. In one embodiment, coatingsare provided to permit either pH-dependent or pH-independent release,e.g., when exposed to gastrointestinal fluid. A pH-dependent coatingserves to release the opioid in desired areas of the gastro-intestinal(GI) tract, e.g., the stomach or small intestine, such that anabsorption profile is provided which is capable of providing at leastabout eight hours and preferably about twelve hours to up to abouttwenty-four hours of analgesia to a patient. When a pH-independentcoating is desired, the coating is designed to achieve optimal releaseof the opioid regardless of pH-changes in the environmental fluid, e.g.,the GI tract. It is also possible to formulate compositions whichrelease a portion of the dose in one desired area of the GI tract, e.g.,the stomach, and release the remainder of the dose in another area ofthe GI tract, e.g., the small intestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the opioid analgesic (with or without theCOX-2 inhibitor) is coated with a hydrophobic material selected from (i)an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.The coating may be applied in the form of an organic or aqueous solutionor dispersion. The coating may be applied to obtain a weight gain fromabout 2 to about 25% of the substrate in order to obtain a desiredsustained release profile. Coatings derived from aqueous dispersions aredescribed, e.g., in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493,assigned to the Assignee of the present invention and herebyincorporated by reference.

Other examples of sustained release formulations and coatings which maybe used in accordance with the present invention include Assignee's U.S.Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, hereby incorporated byreference in their entirety.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

Acrylic Polymers

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the controlled release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Röhm Tech, Inc.There are several different types of Eudragit®. For example, Eudragit® Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit® L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit® S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL andEudragit® RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit® RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a sustainedrelease formulation having a desirable dissolution profile. Desirablesustained release formulations may be obtained, for instance, from aretardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, oneskilled in the art will recognize that other acrylic polymers may alsobe used, such as, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

Processes for Preparing Coated Beads

When a hydrophobic controlled release coating material is used to coatinert pharmaceutical beads such as nu pariel 18/20 beads, which arealready coated with an opioid agonist, a plurality of the resultantsolid controlled release beads may thereafter be placed in a gelatincapsule, with the opioid antagonist in a substantially non-releasableform. The dosage form provides an effective controlled release dose ofthe opioid agonist when ingested and contacted by an environmentalfluid, e.g., gastric fluid or dissolution media.

The controlled release bead formulations of the present invention slowlyrelease the opioid agonist, e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The controlled release profile ofthe formulations of the invention can be altered, for example, byvarying the amount of overcoating with the hydrophobic material,altering the manner in which the plasticizer is added to the hydrophobicmaterial, by varying the amount of plasticizer relative to hydrophobicmaterial, by the inclusion of additional ingredients or excipients, byaltering the method of manufacture, etc. The dissolution profile of theultimate product may also be modified, for example, by increasing ordecreasing the thickness of the retardant coating.

Spheroids or beads coated with an opioid agonist may be prepared, e.g.,by dissolving the drug in water and then spraying the solution onto asubstrate, for example, nu pariel 18/20 beads, using a Wuster insert.Optionally, additional ingredients are also added prior to coating thebeads in order to assist the binding of the opioid to the beads, and/orto color the solution, etc. For example, a product which includeshydroxypropylmethylcellulose, etc. with or without colorant (e.g.,Opadry®, commercially available from Colorcon, Inc.) may be added to thesolution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the therapeutically active agent from the hydrophobiccontrolled release coating. An example of a suitable barrier agent isone which comprises hydroxypropylmethylcellulose. However, anyfilm-former known in the art may be used. It is preferred that thebarrier agent does not affect the dissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

Plasticized hydrophobic material may be applied onto the substratecomprising the therapeutically active agent by spraying using anysuitable spray equipment known in the art. In a preferred method, aWurster fluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid therapeutically active agent when the coated substrate is exposedto aqueous solutions, e.g. gastric fluid, is preferably applied, takinginto account the physical characteristics of the therapeutically activeagent, the manlier of incorporation of the plasticizer, etc. Aftercoating with the hydrophobic material, a further overcoat of afilm-former, such as Opadry®, is optionally applied to the beads. Thisovercoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

The release of the therapeutically active agent from the controlledrelease formulation of the present invention can be further influenced,i.e., adjusted to a desired rate, by the addition of one or morerelease-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of whichare hereby incorporated by reference). The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, etc.

Matrix Formulations

In other embodiments of the present invention, the controlled releaseformulation is achieved via a matrix having a controlled release coatingas set forth above. The present invention also comprisessustained-release tablets comprising an opioid agonist and opioidantagonist particles coated with a coating that renders the antagonistsubstantially non-releasable, wherein the agonist and the antagonist aredispersed in a controlled release matrix that affords in-vitrodissolution rates of the opioid agonist within the preferred ranges andthat releases the opioid agonist in a pH-dependent or pH-independentmanner. The materials suitable for inclusion in a controlled releasematrix will depend on the method used to form the matrix.

For example, a matrix in addition to the opioid agonist and thesubstantially non-releasable form of the coated opioid antagonist, mayinclude:

Hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials; the list is not meantto be exclusive, and any pharmaceutically acceptable hydrophobicmaterial or hydrophilic material which is capable of impartingcontrolled release of the opioid may be used in accordance with thepresent invention.

Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols.

Of these polymers, acrylic polymers, especially Eudragit® RSPO—thecellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form may containbetween 1% and 80% (by weight) of at least one hydrophilic orhydrophobic material.

When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25° and 90° C. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred.The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 60% (by weight) of atleast one polyalkylene glycol.

The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 30° to about 200° C., preferably from about 45° to about 90° C.Specifically, the hydrophobic material may comprise natural or syntheticwaxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl orpreferably cetostearyl alcohol), fatty acids, including but not limitedto fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicaid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about30° to about 100° C.

Suitable hydrophobic materials which may be used in accordance with thepresent invention include digestible, long chain (C₈-C₅₀, especiallyC₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fattyacids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes. Hydrocarbons having amelting point of between 25° and 90° C. are preferred. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

Preferably, a combination of two or more hydrophobic materials areincluded in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably selected from natural andsynthetic waxes, fatty acids, fatty alcohols, and mixtures of the same.Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

One particular suitable matrix comprises at least one water solublehydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂,aliphatic alcohol and, optionally, at least one polyalkylene glycol. Theat least one hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by wt) of theat least one aliphatic alcohol. When at least one polyalkylene glycol ispresent in the oral dosage form, then the combined weight of the atleast one aliphatic alcohol and the at least one polyalkylene glycolpreferably constitutes between 20% and 50% (by wt) of the total dosage.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropyleneglycol or, which is preferred, polyethylene glycol. The number averagemolecular weight of the at least one polyalkylene glycol is preferredbetween 1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, a controlled release matrix mayalso contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Processes for Preparing Matrix-Based Beads

In order to facilitate the preparation of a solid, controlled release,oral dosage form according to this invention, any method of preparing amatrix formulation known to those skilled in the art may be used. Forexample incorporation in the matrix may be effected, for example, by (a)forming granules comprising at least one water soluble hydroxyalkylcellulose and opioid or an opioid salt; (b) mixing the hydroxyalkylcellulose containing granules with at least one C₁₂-C₃₆ aliphaticalcohol; and (c) optionally, compressing and shaping the granules.Preferably, the granules are formed by wet granulating the hydroxy-alkylcellulose/opioid with water. In a particularly preferred embodiment ofthis process, the amount of water added during the wet granulation stepis preferably between 1.5 and 5 times, especially between 1.75 and 3.5times, the dry weight of the opioid.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation ormelt-extrusion techniques, as long as the techniques used do not damagethe integrity of the substantially non-releasable form of the opioidantagonist added during the preparation of the matrix to the extent thatsufficient amount of the opioid antagonist becomes available to bereleased into the gastrointestinal system upon oral administration.Alternatively, the melt extrusion step may be performed with the opioidagonist to produce sustained release particles of the agonist, which maythen be combined with the substantially non-releasable form of theopioid antagonist. Generally, melt-granulation techniques involvemelting a normally solid hydrophobic material, e.g. a wax, andincorporating a powdered drug therein. To obtain a sustained releasedosage form, it may be necessary to incorporate an additionalhydrophobic substance, e.g. ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustainedrelease formulations prepared via melt-granulation techniques are foundin U.S. Pat. No. 4,861,598, assigned to the Assignee of the presentinvention and hereby incorporated by reference in its entirety.

The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g. diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% byweight of the particulate if desired.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theopioid analgesic, together with at least one hydrophobic material andpreferably the additional hydrophobic material to obtain a homogeneousmixture. The homogeneous mixture is then heated to a temperaturesufficient to at least soften the mixture sufficiently to extrude thesame. The resulting homogeneous mixture is then extruded to formstrands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then blendedwith the opioid antagonist particles coated with a coating that rendersthe antagonist substantially non-releasable and divided into unit doses.The extrudate preferably has a diameter of from about 0.1 to about 5 mmand provides sustained release of the opioid agonist for a time periodof from about 8 to about 24 hours.

An optional process for preparing the melt extrusions of the presentinvention includes directly metering into an extruder a hydrophobicmaterial, a therapeutically active agent, and an optional binder;heating the homogenous mixture; extruding the homogenous mixture tothereby form strands; cooling the strands containing the homogeneousmixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and combining the particles with the coated opioidantagonist particles and dividing them into unit doses. In this aspectof the invention, a relatively continuous manufacturing procedure isrealized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic material as described herein. In this regard,the melt-extruded multiparticulates will be of a range of from about 0.1to about 12 mm in length and have a diameter of from about 0.1 to about5 mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size range.Alternatively, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is combined with the coated opioid antagonistparticles and compressed into an oral tablet using conventionaltableting equipment using standard techniques. Techniques andcompositions for making tablets (compressed and molded), capsules (hardand soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

In yet another preferred embodiment, the coated opioid antagonistparticles are added during the extrusion process and the extrudate canbe shaped into tablets as set forth in U.S. Pat. No. 4,957,681(Klimesch, et al.), described in additional detail above and herebyincorporated by reference.

Optionally, the sustained release melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule can be further coated,with a sustained release coating such as the sustained release coatingsdescribed above. Such coatings preferably include a sufficient amount ofhydrophobic material to obtain a weight gain level from about 2 to about30 percent, although the overcoat may be greater depending upon thephysical properties of the particular opioid analgesic compound utilizedand the desired release rate, among other things.

The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded multiparticulates containing oneor more of the therapeutically active agents disclosed above beforebeing encapsulated. Furthermore, the unit dosage forms can also includean amount of an immediate release opioid agonist for prompt therapeuticeffect. The immediate release opioid agonist may be incorporated, e.g.,as separate pellets within a gelatin capsule, or may be coated on thesurface of the multiparticulates after preparation of the dosage forms(e.g., controlled release coating or matrix-based). The unit dosageforms of the present invention may also contain a combination ofcontrolled release beads and matrix multiparticulates to achieve adesired effect.

The sustained release formulations of the present invention preferablyslowly release the opioid agonist, e.g., when ingested and exposed togastric fluids, and then to intestinal fluids. The sustained releaseprofile of the melt-extruded formulations of the invention can bealtered, for example, by varying the amount of retardant, i.e.,hydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the opioid agonist and/or coatedopioid antagonist particles, which are added thereafter to theextrudate. Such formulations typically will have the drugs blendedtogether with the extruded matrix material, and then the mixture wouldbe tableted in order to provide a slow release of the opioid agonist.Such formulations may be advantageous, for example, when thetherapeutically active agent included in the formulation is sensitive totemperatures needed for softening the hydrophobic material and/or theretardant material.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

Example 1

In Example 1, a substantially non-releasable form of an opioidantagonist (naltrexone HCl) is prepared by coating naltrexone particleswith a coating that renders the antagonist substantially non-releasable.

Formula:

Amt/unit Ingredients (mg) LOADING Naltrexone HCl 5.0 Sugar Spheres(30/35 50.0 mesh) Opadry White Y-5-7068 2.5 Purified Water 42.5*OVERCOATING Opadry White Y-5-7068 3.02 Purified Water 17.11* NON-RELEASECOATING (FOR RENDERING OPIOID ANTAGONIST SUBSTANTIALLY NON-RELEASABLE)Eudragit RS30D (dry wt.) 12.10 Triethyl Citrate 2.42 Talc 4.84 PurifiedWater 49.21* OVERCOATING Opadry White Y-5-7068 4.12 Purified Water23.35* Total 84.0 *Remains in product as residual moisture only.Process:

1. Solution Dissolve the Naltrexone HCl in Purified Water. OncePreperation dissolved, add the Opadry White and continue mixing until ahomogeneous dispersion is yielded. 2. Loading Apply the above dispersiononto the Sugar Spheres using a fluid bed coating machine. 3. OvercoatingPrepare an overcoating solution by dispersing Opadry White in PurifiedWater. Apply this dispersion over the sugar spheres loaded withNaltrexone HCl using a fluid bed coating machine. 4. Retardant Preparethe non-release coating solution by mixing Coating the Eudragit RS30D,Triethyl Citrate, Talc, and Purified Water. Apply this dispersion overthe loaded and overcoated sugar spheres using a fluid bed coatingmachine. 5. Overcoating Prepare a second overcoating solution bydispersing Opadry White in Purified Water. Apply this dispersion overthe non-release coated naltrexone spheres using a fluid bed coatingmachine 6. Curing Cure the spheres at 45° C. for approximately 48 hours.

Example 2

In Example 2, a substantially non-releasable form of an opioidantagonist (naltrexone HCl) is prepared as naltrexone HCl containinggranulates. The granulates are comprised of naltrexone HCl dispersed ina matrix that renders the antagonist substantially non-releasable.

Formula:

Amt/unit Ingredient (mg) Naltrexone HCl 5.0 Dicalcium Phosphate 53.0Poly (DI-Lactide-Co- 12.0 Glycolide) polymer (PLGA) MW~100,000 EthylAcetate Total 70.0 *Used as a vehicle for application of PLGA polymer.Process:

1. Solution Dissolve PLGA in Ethyl Acetate by mixing. Preparation 2.Granulation Place the Naltrexone HCl, and Dicalcium Phosphate in a fluidbed coating machine and granulate by spraying the above solution.

Example 3

In Example 3, a substantially non-releasable form of an opioidantagonist (naltrexone HCl) is prepared as naltrexone HCl extrudedpellets.

Formula:

Amt/unit Ingredient (mg) Naltrexone HCl 5.0 Eudragit RSPO 180.0 StearylAlcohol 55.0 Total 240.0Process:

1. Milling Pass stearyl alcohol flakes through an impact mill. 2.Blending Mix Naltrexone HCl, Eudragit, and milled Stearyl Alcohol in atwin shell blender. 3. Extrusion Continuously feed the blended materialinto a twin screw extruder and collect the resultant strands on aconveyor. 4. Cooling Allow the strands to cool on the conveyor. 5.Pelletizing Cut the cooled strands into pellets using a Pelletizer. 6.Screening Screen the pellets and collect desired sieve portion.

Example 4 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Beads

Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 Stearyl Alcohol44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered) MicrocrystallineCellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HCl Beads 84.0(Example 1) Magnesium Stearate 2.0 Opadry Red 10.0 Purified Water 56.7*Total 314.0 *Remains in product as residual moisture only.Process:

1. Milling Pass the Stearyl Alcohol flakes through an occillating mill.2. Blending Mix the Hydrocodone Bitartrate, milled Stearyl Alcohol;Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, and GlycerylBehenate in a twin shell blender. 3. Extrusion Continuously feed theblended material into a twin screw extruder and collect the resultantheated material on a conveyor. 4. Cooling Allow the extrudate to cool onthe conveyor. 5. Milling Mill the cooled extrudate using an occillatingmill. 6. Blending Blend the milled extrudate, naltrexone HCl beads (fromExample 1), and Magnesium Stearate. 7. Compression Compress theresultant granulation using a tablet press. 8. Coating Prepare a filmcoating solution by dispersing the Opadry in Purified Water and applyingit to the tablet cores.

Example 5 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Granulation

Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 Stearyl Alcohol44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered) MicrocrystallineCellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HCl 70.0 Granulation(Bxample 2) Magnesium Stearate 2.0 Opadry Red 10.0 Purified Water 56.7*Total 300.0 *Remains in product as residual moisture only.Process:

1. Milling Pass the Stearyl Alcohol flakes through an occillating mill.2. Blending Mix the Hydrocodone Bitartrate, milled Stearyl Alcohol,Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, and GlycerylBehenate in a twin shell blender. 3. Extrusion Continuously feed theblended material into a twin screw extruder and collect the resultantheated material on a conveyor. 4. Cooling Allow the extrudate to cool onthe conveyor. 5. Milling Mill the cooled extnidate using an occillatingmill. 6. Blending Blend the milled extrudate, Naltrexone HCl granulation(from Example 2), and Magnesium Stearate. 7. Compression Compress theresultant granulation using a tablet press. 8. Coating Prepare a filmcoating solution by dispersing the Opadry in Purified Water and applyingit to the tablet cores.

Example 6 Oxycodone HCl-Controlled Release Tablets with Naltrexone HClBeads

Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose 59.25Povidone 5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin 2.00 StearylAlcohol 25.00 Talc 2.50 Magnesium Stearate 1.25 Naltrexone HCl Beads84.00. (Example 1) Opadry Pink 6.00 Purified Water 34.00* Total 215.00*Remains in product as residual moisture only.Process:

1. Solution Plasticize the Eudragit with Triacetin by mixing.Preperation 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, andPovidone into a fluid bed granulator and apply the above solution. 3.Milling Pass the granulation through a rotating impeller mill. 4. DryingDry granulation if moisture content is too high. 5. Waxing Melt StearylAlcohol and wax the above granulation by adding melted Stearyl Alcoholonto granulation while mixing. 6. Cooling Cool the waxed granulation ina fluid bed dryer. 7. Milling Pass the cooled waxed granulation througha rotating impeller mill. 8. Blending Blend the milled waxedgranulation, Talc, Magnesium Stearate, and Naltrexone HCl beads (fromExample 1). 9. Compression Compress the resultant granulation using atablet press 10. Coating Prepare a film coating solution by dispersingthe Opadry in Purified Water and applying it to the tablet cores.

Example 7 Oxycodone HCl-Controlled Release Tablets with Naltrexone HClGranulation

Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose 59.25Povidone 5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin 2.00 StearylAlcohol 25.00 Talc 2.50 Magnesium Stearate 1.25 Naltrexone HCl 70.00Granulation (Example 2) Opadry Pink 6.00 Purified Water 34.00* Total201.00 *Remains in product as residual moisture only.Process:

1. Solution Plasticize the Eudragit with Triacetin by mixing.Preperation 2. Granulation Place Oxycodone HCl, Spray Dried Lactose andPovidone into a fluid bed granulator and apply the above solution. 3.Milling Pass the granulation through a rotating impeller mill. 4. DryingDry granulation if moisture content is too high. 5. Waxing Melt StearylAlcohol and wax the above granulation by adding melted Stearyl Alcoholonto granulation while mixing. 6. Cooling Cool the waxed granulation ina fluid bed dryer. 7. Milling Pass the cooled waxed granulation througha rotating impeller mill. 8. Blending Blend the milled waxedgranulation, Talc, Magnesium Stearate, and Naltrexone HCl granulation(from Example 2). 9. Compression Compress the resultant granulationusing a tablet press. 10. Coating Prepare a film coating solution bydispersing the Opadry in Purified Water and applying it to the tabletcores.

Example 8 Hydromorphone HCl-Controlled Release Capsules with NaltrexoneHCl Extruded Pellets

Formula:

Amt/unit Ingredient (mg) Hydromorphone HCl 12.0 Eudragit RSPO 76.5Ethylcellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HCl Pellets 240.0(Example 3) Hard Gelatin Capsules ✓ Total 360.0Process:

1. Milling Pass Stearyl Alcohol flakes through an impact mill. 2.Blending Mix Hydromorphone HCl, Eudragit, Ethycellulose and milledStearyl Alcohol in a twin shell blender. 3. Extrusion Continuously feedthe blended material into a twin screw extruder and, collect theresultant strands on a conveyor. 4. Cooling Allow the strands to cool onthe conveyor. 5. Pelletizing Cut the cooled strands into pellets using aPelletizer. 6. Screening Screen the pellets and collect desired sieveportion. 7. Encapsulation Fill the extruded Hydromorphone HCl pellets at120 mg and Naltrexone HCl pellets (from Example 3) at 240 mg into hardgelatin capsules.

Example 9 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Beads

Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 Stearyl Alcohol44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered) MicrocrystallineCellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HCl Beads 84.0(Example 1) Magnesium Stearate 2.0 Opadry Red 10.0 Purified Water 56.7*Total 314 *Remains in product as residual moisture only.Process:

1. Milling Pass the Stearyl Alcohol flakes through an occillating mill.2. Blending Mix the Hydrocodone Bitartrate, milled Stearyl Alcohol,Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, and GlycerylBehenate in a twin shell blender. 3. Extrusion Continuously feed theblended material into a twin screw extruder and collect the resultantheated material on a conveyor. 4. Cooling Allow the extrudate to cool onthe conveyor. 5. Milling Mill the cooled extnidate using an occillatingmill. 6. Blending Blend the milled extrudate, Naltrexone HCl beads (fromExample 1), and Magnesium Stearate. 7. Compression Compress theresultant granulation using a tablet press. 8. Coating Prepare a filmcoating solution by dispersing the Opadry in Purified Water and applyingit to the tablet cores.

Example 10 Hydrocodone Bitartrate Controlled Release Tablets withNaltrexone HCl Granulation

Amt/unit Ingredient (mg) Hydrocodone Bitartrate 30.0 Stearyl Alcohol44.0 Anhydrous Dicalcium 62.0 Phosphate (Powdered) MicrocrystallineCellulose 62.0 Glyceryl Behenate 20.0 Naltrexone HCl 70.0 Granulation(Example 2) Magnesium Stearate 2.0 Opadry Red 10.0 Purified Water 56.7*Total 300.5 *Remains in product as residual moisture only.Process:

1. Milling Pass the Stearyl Alcohol flakes through an occillating mill.2. Blending Mix the Hydrocodone Bitartrate, milled Stearyl Alcohol,Anhydrous Dicalcium Phosphate, Microcrystalline Cellulose, and GlycerylBehenate in a twin shell blender. 3. Extrusion Continuously feed theblended material into a twin screw extruder and collect the resultantheated material on a conveyor. 4. Cooling Allow the extrudate to cool onthe conveyor. 5. Milling Mill the cooled extrudate using an occillatingmill. 6. Blending Blend the milled extrudate, Naltrexone HCl granulation(from Example 2), and Magnesium Stearate. 7. Compression Compress theresultant granulation using a tablet press. 8. Coating Prepare a filmcoating solution by dispersing the Opadry in Purified Water and applyingit to the tablet cores.

Example 11 Oxycodone HCl-Controlled Release Tablets with Naltrexone HClBeads

Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose 58.75Povidone 5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin 2.00 StearylAlcohol 25.00 Talc 2.50 Magnesium Stearate 1.25 Naltrexone HCl Beads84.00 (Example 1) Opadry Pink 6.00 Purified Water 34.00* Total 215.00*Remains in product as residual moisture only.Process:

1. Solution Plasticize the Eudragit with Triacetin by mixing.Preparation 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, andPovidone into a fluid bed granulator and apply the above solution. 3.Milling Pass the granulation through a rotating impeller mill. 4. DryingDry granulation if moisture content is too high. 5. Waxing Melt StearylAlcohol and wax the above granulation by adding melted Stearyl Alcoholonto granulation while mixing. 6. Cooling Cool the waxed granulation ina fluid bed dryer. 7. Milling Pass the cooled waxed granulation througha rotating impeller mill. 8. Blending Blend the milled waxedgranulation, Talc, Magnesium Stearate, and Naltrexone HCl beads (fromExample 1). 9. Compression Compress the resultant granulation using atablet press. 10. Coating Prepare a film coating solution by dispersingthe Opadry in Purified Water and applying it to the tablet cores.

Example 12 Oxycodone HCl-Controlled Release Tablets with Naltrexone HClGranulation

Amt/unit Ingredient (mg) Oxycodone HCl 20.00 Spray Dried Lactose 58.75Povidone 5.00 Eudragit RS 30D (dry wt.) 10.00 Triacetin 2.00 StearylAlcohol 25.00 Talc 2.50 Magnesium Stearate 1.25 Naltrexone HCl 70.00Granulation (Example 2) Opadry Pink 6.00 Purified Water 34.00* Total201.00 *Remains in product as residual moisture only.Process:

1. Solution Plasticize the Eudragit with Triacetin by mixing.Preparation 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, andPovidone into a fluid bed granulator and apply the above solution. 3.Milling Pass the granulation through a rotating impeller mill. 4. DryingDry granulation if moisture content is too high. 5. Waxing Melt StearylAlcohol and wax the above granulation by adding melted Stearyl Alcoholonto granulation while mixing. 6. Cooling Cool the waxed granulation ina fluid bed dryer. 7. Milling Pass the cooled waxed granulation througha rotating impeller mill. 8. Blending Blend the milled waxedgranulation, Talc, Magnesium Stearate, and Naltrexone HCl granulation(from Example 2). 9. Compression Compress the resultant granulationusing a tablet press. 10. Coating Prepare a film coating solution bydispersing the Opadry in Purified Water and applying it to the tabletcores.

Example 13 Hydromorphone HCl-Controlled Release Capsules with NaltrexoneHCl Extruded Pellets

Formula:

Amt/unit Ingredient (mg) Hydromorphone HCl 12.0 Eudragit RSPO 76.0Ethylcellulose 4.5 Stearyl Alcohol 27.0 Naltrexone hCl Pellets 240.0(Example 3) Hard Gelatin Capsules ✓ Total 360.0Process:

1. Milling Pass stearyl alcohol flakes through an impact mill. 2.Blending Mix Hydromorphone HCl, Eudragit, Ethycellulose and milledStearyl Alcohol in a twin shell blender. 3. Extrusion Continuously feedthe blended material into a twin screw extruder and collect theresultant strands on a conveyor. 4. Cooling Allow the strands to cool ona Conveyor. 5. Pelletizing Cut the cooled strands into pellets using aPelletizer. 6. Screening Screen the pellets and collect desired sieveportion. 7. Encapsulation Fill the extended Hydromorphone HCl pellets at120.0 mg and Naltrexone HCl pellets (from Example 3) at 240 mg into hardgelatin capsules.

Example 14

Controlled Release Oxycodone Hydrochloride 10 mg Tablets—OrganicManufacture Oxycodone hydrochloride (10 mg/tablet) and spray driedlactose (71.25 mg/tablet) are transferred into an appropriate sizedmixer and mix for approximately 6 minutes. Eudragit® RS PM powder (6mg/tablet) is dispersed in ethanol. While the powders are mixing, thepowders are granulated with the dispersion and the mixing continueduntil a moist granular mass is formed. Additional ethanol is added ifneeded to reach granulation end point. The granulation is transferred toa fluid bed dryer and dried at 30 C, and then passed through a 12-meshscreen. The remaining Eudragit® RS PM (9 mg/tablet) is dispersed in asolvent of 90 parts ethanol and 10 parts purified water; and sprayedonto the granules in the fluid bed granulator/dryer at 30 C. Next, thegranulate is passed through a 12-mesh screen. Stearyl alcohol (25mg/tablet) is melted at approximately 60-70 C. The warm granules arereturned to the mixer. While mixing, the melted stearyl alcohol isadded. The coated granules are removed from the mixer and allowed tocool. Thereafter, they are passed through a 12-mesh screen. Next, thegranulate is mixed with naloxone particles (approximately 1-5 mg pertablet) coated with a coating that renders naloxone substantiallynon-releasable, and pharmaceutically desirable tabletting excipients,e.g., talc and magnesium stearate in a suitable blender and compressedinto tablets.

The naloxone particles have a diameter of about 0.5 to 2 mm. Thenaloxone particles coated with a coating that renders naloxonesubstantially non-releasable may be prepared by spraying onto theparticles the coating composition comprising a cellulose polymer or anacrylic polymer that is insoluble in water and impermeable to naloxone.The suitable particles include granules, pellets, spheroids or beadscomprising naloxone. When the particles are beads or pellets, they maybe prepared by dissolving the naloxone in a solution and spraying itonto inert pellets or beads.

Preferably, the coating composition comprises Eudragit® RS, which may beused in the form of an aqueous suspension and in combination with aplasticizer such as, e.g., acetyl triethylcitrate and/or acetyl tributylcitrate.

Preferably, the coating composition comprises Eudragit® RS, which may beused in the form of an aqueous suspension and in combination with aplasticizer such as, e.g., acetyl triethylcitrate and/or acetyl tributylcitrate.

Example 15 Method of Treating Pain

The oral dosage form according to the present invention may beadministered to a patient to provide pain relief. The oral dosage formmay comprise an orally effective amount of an opioid agonist and anopioid antagonist that is rendered substantially non-releasable.

When the oral dosage form is administered orally and delivered to thegastrointestinal tract of a patient in need of pain therapy, the opioidagonist is released from the dosage form during normal digestion,providing analgesia to the patient. But the opioid antagonist, becauseit has been rendered substantially non-releasable is substantially notreleased during its transit through the gastrointestinal system.Preferably, the substantially non-releasable form of the antagonist isresistant to laxatives (mineral oil) used to manage delayed colonictransit, or achlorhydria states. Patients who take the oral dosage formas directed, without tampering with it (e.g. by mechanical agitation,heating, or dissolution in a solvent), will not have the opioidantagonist absorbed in sufficient amount during any time interval duringthe dosing of the formulation such that the analgesic effectiveness ofthe opioid agonist is reduced or eliminated by the antagonist. In otherwords, the amount of opioid antagonist released from the dosage form(when orally administered intact) and absorbed from the gastrointestinaltract and accumulated in the patient's body, does not rise to a levelwhich significantly impacts or changes on the analgesic efficacy of thedose of opioid agonist included in the dosage form.

Example 16 Method of Preventing Abuse of an Opioid Agonist

The oral dosage form according to the present invention may be used toprevent the abuse potential of an opioid agonist contained therein. Theoral dosage form comprises an opioid agonist in combination with anopioid antagonist. The opioid antagonist is present in a form that issubstantially non-releasable during digestion. Thus, when the oraldosage form is delivered to the gastrointestinal tract orally asintended, without having been tampered with, the antagonist issubstantially prevented from being released into the gastrointestinalsystem. But if the oral dosage form is tampered with, e.g., bymechanical agitation (e.g., crushing, shearing, grinding), heat (e.g.,temperatures of greater than 45 C., preferably between 45 to 50 C), ordissolution of the dosage form in a solvent (with or without heating),the dosage form is tainted by the opioid antagonist, which is now madeavailable to blunt the opioid effects. Thus, when the dosage form ischewed, crushed, heated or dissolved in a solvent, and then administeredorally, intranasally, parenterally or sublingually, the effect of theopioid agonist is at least partially blocked by the opioid antagonist.

Example 17

In this human study, 12 morphine-dependent subjects were evaluated forprecipitated withdrawal after administration of hydrocodone immediaterelease tablets given concomitantly with a dose of naltrexone rangingfrom 0.25 to 8 mg. The experimental design was single blind,single-dose, placebo-controlled with an ascending naltrexone dose. Afteradministration of the study medications, subjective and physiologicalmeasurements of abuse liability and withdrawal were made across a32-fold range of naltrexone doses. The data suggest that at a 1 mgnaltrexone dose, opioid-dependent subjects demonstrate less liking ofthe agonist relative to the combination with placebo and achieved aplasma concentration resulting in 50% of the maximal withdrawal symptomscore.

Example 18

This was a randomized, double blind placebo controlled trial examiningthe threshold of withdrawal induced by immediate-release naltrexone in12 methadone-dependent subjects. While the study was in progress, aninterim analysis shows that 0.5 mg of naltrexone was able to elicit thesigns and symptoms of withdrawal in this population. These studiessuggest that the dose of naltrexone needed to elicit withdrawal symptomsin opioid dependent subjects lies between 0.25 and 1 mg.

Example 19

This is a randomized single blind, single dose, placebo controlled10-way crossover trial examining the effect of naltrexone on thesubjective and physiological effects of 15 mg hydrocodone in 16 normalsubjects. Doses of naltrexone ranged from 0.4 to 12.8 mg. In this study,0.4 mg of naltrexone was able to antagonize several of the centrallymediated opioid effects of hydrocodone, including pupillary meiosis.Based on this data, substantially lower doses below 0.25 mg ofnaltrexone will demonstrate little antagonism of the concomitantagonist. This is supported by the absence of withdrawal signs observedin subjects in example 17 receiving the 0.25-mg.

The clinical data for examples 17, 18 and 19 suggest that bio-available,immediate-release doses of 0.125 mg of naltrexone (or equivalent promptrelease from a controlled release dosage form) will not affect analgesiato any significant degree, while larger prompt release of bio-availabledrug (0.25 mg or greater) will do so. These clinical data show that aloading of naltrexone into the opioid matrix for this example at a ratioof 1:15 to 1:30 mg naltrexone/mg hydrocodone, and that thetampered/intact release ratio is at least 4:1 and preferably higher. Oralternatively, it can be defined that less than 0.25 mg of naltrexone isreleased from the intact dosage form, and 0.25 mg or greater naltrexoneis released from the crushed dosage form.

Example 20 Naltrexone HCl Beads

Formula:

Amt/unit Ingredients (mg) Step 1. Drug layering Naltrexone HCl 0.6Non-pareil beads (30/35 mesh) 61.4 Opadry Clear 0.6 (Hydroxypropymethylcellulose) Water Step 2. Anionic polymer Eudragit L30D (dry) 6.3 coatTributyl Citrate 1.6 Talc 3.1 Water (evaporates during process) Step 3.Sustained release Eudragit RS30D (dry) 17.9 coat Tributyl citrate 4.5Talc 8.8 Water (evaporate during process) Step 4. Seal coat Opadry Clear3.2 (Hydroxypropylmethyl cellulose) Water (evaporates during process)Total (on dry basis) 108Bead Manufacturing Procedure

-   1. Dissolve naltrexone HCl and Opadry Clear in water. Spray the drug    solution onto non-pareil beads in a fluid bed coater with Wurster    insert.-   2. Disperse Eudragit L30D, Tributyl citrate, and talc in water.    Spray the dispersion onto the drug-loaded beads in the fluid bed    coater.-   3. Disperse Eudragit RS30D, tributyl citrate, and talc in water.    Spray the dispersion onto the beads in the fluid bed coater.-   4. Dissolve Opadry Clear in water. Spray the solution onto the beads    in the fluid bed coater.-   5. Cure the beads at 60° C. for 24 hours.    Dissolution Method    1. Apparatus-USP Type II (Paddle), 75 rpm at 37° C.    2. Sampling Time: 1, 2, 4, 8, 12, 24, 36    3. Media: SGF for one hour/SIF thereafter    Analytical Method: High Performance Liquid Chromatography    Results and Discussion:    The beads (108 mg) were found to have the following dissolution    results:

Time (hr) 1 2 4 12 24 36 Mean % nd nd nd nd 6.0 10.0 dissolved nd = nonedetected

The dissolution results show that only about 10% naltrexone HCl (0.06mg) of naltrexone HCl was released after 36 hours in the dissolutionbath. These beads will not be bioavailable if taken unbroken orally.

Naltrexone HCl is very water-soluble. It tends to migrate through thesustained release film during aqueous film coating process (step 3). Ifmigration occurs during this coating step, the film will become porousduring dissolution and the drug release rate would be relatively rapid.The anionic coating (step 2) forms a water insoluble complex layer withthe protonated naltrexone HCl salt and would prevent the drug frommigrating through the subsequent sustained release coating.

Dissolution of Broken Beads

Simulated Tampering Process

About 108 mg of naltrexone beads was ground in a mortar and pestle topowder for the dissolution study.

Dissolution Method—same as above

Results and Discussion:

The broken beads (108 mg) were found to have the following dissolutionresults:

Time (hr) 0.25 0.5 1 Mean % 91 100 104 dissolved

We can thus see at hour 1, from the intact beads, there is no detectableNTX released, yet when crushed, all the NTX, 0.6 mg is released. This isgraphically represented in FIG. 1. Thus the ratio of crushed/intact athour 1 is 100:0 and this is greater than the criteria of >4:1 asconcluded from examples 17, 18 and 19.

Example 21 Oxycodone IR Capsules with Naltrexone Beads

Formula:

Amt/unit* Ingredients (mg) Step 1. Drug layering Oxycodone HCl 5.0Non-pareil beads (30/35 mesh) 1.25 Hydroxypropymethyl cellulose 54.35(HPMC) Water (evaporates during process) Step 2. Film Coat OpadryButterscotch 1.9 Water (evaporate during process) Step 3. EncapsulationOxyIR beads (step 2) 62.5 Naltrexone beads (Example 20)* 108 *To blindthe OxyIR beads, the naltrexone beads would need to use OpadryButterscotch as the seal coat in Step 4, Example 20.Manufacturing Procedure

-   1. Dissolve oxycodone HCl and HPMC in water. Spray the drug solution    onto non-pareil beads in a fluid bed coater with Wurster insert.-   2. Dissolve the colored Opadry in water. Film coat the drug-loaded    beads in the fluid bed coater.-   3. Mix equal amount of OxyIR beads and naltrexone beads. Encapsulate    in hard gelatin capsules.

Example 22 Morphine Sulfate Controlled Release Capsules with NaltrexoneBeads

Formula:

Amt/unit* Ingredients (mg) Step 1. Drug loading Morphine sulfate 60.0Lactose impalpable 12.0 Eudragit RS30D 2.0 Povidone 3.5 Nupareil PG30/35 16.8 Opadry blue 4.9 Water Step 2. Controlled MSIR beads (step 1)99.2 Release Coat Eudragit RS 30D 4.712 Eudragit RL 30D 0.248 Triethylcitrate 0.992 Talc 1.884 Opadry blue 5.639 Water Step 3. EncapsulationMSCR beads (above) 212 Naltrexone beads (Example 20)* 108 *To blind theMSCR beads, the naltrexone beads would need to use Opadry blue as theseal coat in Step 4; Example 22.Manufacturing Procedure

-   1. Disperse povidone and Eudragit RS30D in water. Blend morphine    sulfate and lactose.-   2. Load beads in Rotor processor. Spray the drug powder blend and    the binder solution onto beads.-   3. Film-coat the above beads in the Rotor processor.-   4. Disperse Eudragit RS30D, RL 30D, Triethyl citrate, talc and    triethyl citrate in water. Coat the above beads in a fluid bed    coated with Wurster insert.-   5. Cure the beads (MSCR beads).-   6. Mix equal amount of MSCR beads and naltrexone beads. Encapsulate    in hard gelatin capsules.

Example 23 Naltrexone HCl Extruded Pellets

Formula:

Amt/unit Ingredient (mg) Naltrexone HCl 2.0 Eudragit RSPO 88.0 StearylAlcohol 15.0 Stearic Acid 15.0 Butylated Hydroxytoluene 1.0 (BUT) Total121.0Process:

1. Milling Pass stearyl alcohol flakes through a mill. 2. Blending MixNaltrexone HCl, Eudragit, milled Stearyl Alcohol, Stearic Acid and BHTin a twin shell blender. 3. Extrusion Continuously feed the blendedmaterial into a twin screw extruder and collect the resultant strands ona conveyor. 4. Cooling Allow the strands to cool on a Conveyor. 5.Pelletizing Cut the cooled strands into 1 mm pellets using a Pelletizer.6. Screening Screen the pellets and collect desired sieve portion.Dissolution Method1. Apparatus-USP Type II (Paddle), 75 rpm at 37° C.2. Sampling Time: 1, 2, 4, 8, 12, 24, 363. Media: SGF for one hour/SIF thereafter4. Analytical Method: High Performance Liquid ChromatographyResults:

Time (hour) 1 2 4 8 12 24 36 Mean % Dissolved 1.3 2.6 2.9 3.6 4.0 5.26.2Simulated Tampering ProcessNaltrexone Pellets were ground in a mortar and pestle to powder for thedissolution study.Dissolution Method: Same as aboveResults:

Time (hour). 1 Mean % Dissolved 33.5

Thus the release of the intact pellets is 0.026 mg at hour 1, and whencrushed is 0.67 mg at hour 1. This ratio of crushed to intact is alsogreater than 4:1. This is graphically represented in FIG. 2.

Example 24 Naltrexone HCl Extruded Pellets

Formula:

Amt/unit Ingredient (mg) Naltrexone HCl 2.0 Eudragit RSPO 96.0 StearylAlcohol 22.0 Dibasic Calcium 6.0 Phosphate Butylated Hydroxytoluene 1.0(BHT) Total 127.0Process:

1. Milling Pass stearyl alcohol flakes through a mill. 2. Blending MixNaltrexone HCl, Eudragit, milled Stearyl Alcohol, Dibasic CalciumPhosphate and BHT in a twin shell blender. 3. Extrusion Continuouslyfeed the blended material into a twin screw extruder and collect theresultant strands, on a conveyor. 4. Cooling Allow the strands to cool aConveyor. 5. Pelletizing Cut the cooled strands into pellets using aPelletizer. 6. Screening Screen the pellets and collect desired sieveportion.Dissolution Method4. Apparatus-USP Type II (Paddle), 75 rpm at 37° C.5. Sampling Time: 1, 2, 4, 8, 12, 24, 366. Media: SGF for one hour/SIF thereafter7. Analytical Method: High Performance Liquid ChromatographyResults:

Time (hour) 1 2 4 8 12 24 36 Mean % Dissolved 3.1 5.9 8.9 12.2 14.7 19.924.6Simulated Tampering ProcessNaltrexone Pellets were ground in a mortar and pestle to powder for thedissolution study.Dissolution Method: Same as aboveResults:

Time (hour) 1 Mean % Dissolved 36.4

Thus the release of the intact pellets is 0.062 mg at hour 1, and whencrushed is 0.728 mg at hour 1. This ratio of crushed to intact is alsogreater than 4:1. This is graphically represented in FIG. 3.

Example 25 Possible Hydromorphone HCl-CR Capsules with Naltrexone HClExtruded Pellets

Formula:

Amt/unit Ingredient (mg) Hydromorphone HCl 12.0 Eudragit RSPO 76.5Ethylcellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HCl Pellets 121.0(Example 23) Hard Gelatin Capsules ✓ Total 241.0Process:

1. Milling Pass Stearyl Alcohol flakes through an impact mill. 2.Blending Mix Hydromorphone HCl, Eudragit, Ethycellulose and milledStearyl Alcohol in a twin shell blender. 3. Extrusion Continuously feedthe blended material into a twin screw extruder and collect theresultant strands on a conveyor. 4. Cooling Allow the strands to cool aConveyor. 5. Pelletizing Cut the cooled strands into pellets using aPelletizer. 6. Screening Screen the pellets and collect desired sieveportion. 7. Encapsulation Fill the extruded Hydromorphone HCl pellets at120 mg and Naltrexone pellets (from example 23) at 121 mg into hardgelatin capsules.

Example 26 Possible Hydromorphone HCl-CR Capsules with Naltrexone HClExtruded Pellets

Formula:

Amt/unit Ingredient (mg) Hydromorphone HC1 12.0 Eudragit RSPO 76.5Ethylcellulose 4.5 Stearyl Alcohol 27.0 Naltrexone HCl Pellets 127.0(Example 24) Hard Gelatin Capsules ✓ Total 247.0Process:

1. Milling Pass Stearyl Alcohol flakes through an impact mill. 2.Blending Mix Hydromorphone HCl, Eudragit, Ethycellulose and milledStearyl Alcohol in a twin shell blender. 3. Extrusion Continuously feedthe blended material into a twin screw extruder and collect theresultant strands on a conveyor. 4. Cooling Allow the strands to cool aConveyor. 5. Pelletizing Cut the cooled strands into pellets using aPelletizer. 6. Screening Screen the pellets and collect desired sieveportion. 7. Encapsulation Fill the extruded Hydromorphone HCl pellets at120 mg and Naltrexone pellets (from example 24) at 127 mg into hardgelatin capsules.

Example 27A Naltrexone CR Beads

A Naltrexone controlled release bead is developed which can beincorporated into opioid controlled release granulation and the mixtureis then compressed into tablets. Oxycodone HCl controlled releasegranulation is used with naltrexone beads as an example.

Formula 27A.

Amt/unit* Ingredients (mg) Step 1. Drug layering Naltrexone HCl 3.3Non-pared beads (14/18 mesh) 95.0 Plasdone C30 1.5 Talc 0.2 Water Step2. Seal coat Opadry Clear 5.0 (Hydroypropylmethyl) cellulose) Water Step3. Sustained release Eudragit RS30D (dry) 17.63 coat Tributyl citrate3.53 Tween 80 0.04 Talc 8.81 Water Step 4. Seal coat Opadry Clear 5.0(Hydroxypropylmethyl cellulose) Water Total 140Bead Manufacturing Procedure

-   1. Dissolve naltrexone HCl and HPMC in water. Spray the drug    solution onto non-pareil beads in a fluid bed coater with Wurster    insert.-   2. Disperse Eudragit L, Tributyl citrate, and talc in water. Spray    the dispersion onto the drug-loaded beads in the fluid bed coater.-   3. Disperse Eudragit RS, tributyl citrate, and talc in water. Spray    the dispersion onto the beads in the fluid bed coater.-   4. Dissolve HPMC in water. Spray the solution onto the beads in the    fluid bed coater.-   5. Cure the beads at 60° C. for 24 hours.    Dissolution Method    1. Apparatus-USP Type II (Paddle), 75 rpm at 37° C.    2. Sampling Time: 1, 2, 4, 8, 12, 24, 36    3. Media: SGF for one hour/SIF thereafter    4. Analytical Method: High Performance Liquid Chromatography    Results and Discussion:    Naltrexone Dissolution from Intact Beads

Time (hr) 1 4 8 12 24 36 Mean % 2 2 4 5 6 33 dissolvedNaltrexone Dissolution from Crushed Beads

Time (hr) 1 Mean % 100 dissolvedFormula 27B Oxy/NX CR Tablet

Amt/unit* Ingredients (mg) Step 1. Granulation Oxycodone HCl 10.0 SprayDried Lactose 69.25 Povidone 5.0 Eudragit RS30D (dry) 10.0 Triacetin 2.0Stearyl alcohol 25.0 Talc 2.5 Magnesium 1.25 Step 2. CombinationOxyContin granulation (above) 125 tablet Naltrexone CR beads (Formula140 27A)Manufacturing Procedure (Oxy/NX CR Tablet)

-   1. Spray the Eudragit/triacetin dispersion onto the Oxycodone HCl,    spray dried lactose and povidone using a fluid bed granulator.-   2. Discharge the granulation and pass through a mill.-   3. Melt the stearyl alcohol and add to the milled granulation using    a mill. Allow to cool.-   4. Pass the cooled granulation through a mill.-   5. Lubricate the granulation with talc and magnesium stearate. Using    a mixer.-   6. Mix naltrexone beads with the above granulation and compress into    tablets.    Dissolution Method    1. Apparatus-USP Type II (Paddle), 50 rpm at 37° C.    2. Sampling Time: 1, 2, 4, 8, 12, 24, 36    3. Media: 900 ml pH 6.5 phosphate buffer    4. Analytical Method: High Performance Liquid Chromatography    The Oxy/NX CR tablets were found to have the following dissolution    results:    Naltrexone Dissolution from Intact Tablet

Time (hr) 1 4 8 12 24 36 Mean % 1 3 9 15 25 36 dissolvedNaltrexone Dissolution from Crushed Tablet

Time (hr) 1 Mean % 95 dissolved

1. A composition comprising an opioid antagonist and from about 93% toabout 98% of a hydrophobic material by weight of the composition, withthe proviso that the composition does not comprise an opioid agonist,wherein the hydrophobic material sequesters the antagonist such that,upon inclusion into a solid oral dosage form containing an opioidagonist, an amount of the antagonist released from said dosage formwhich has been orally administered intact is less than an amountbioequivalent to 0.125 mg of naltrexone, based on the in-vitrodissolution at 1 hour of the dosage form in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37° C., and isinsufficient to produce an antagonist effect of the antagonist, but anamount of the antagonist released from said dosage form which has beentampered with and administered orally, intranasally, parenterally orsublingually is bioequivalent to 0.25 mg of naltrexone or more, based onthe in-vitro dissolution at 1 hour of the dosage form in 900 ml ofSimulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpmat 37° C., and will substantially block an effect of the agonist; theintact dosage form releasing less than 15% by weight of the opioidantagonist within 36 hours, based on the in-vitro dissolution in adissolution bath, wherein the antagonist is dispersed in a matrix ofsaid hydrophobic material.
 2. A composition consisting essentially of anopioid antagonist and from about 93% to about 98% of a hydrophobicmaterial, wherein the hydrophobic material sequesters the antagonistsuch that, upon inclusion into a solid oral dosage form containing anopioid agonist, an amount of the antagonist released from said dosageform which has been orally administered intact is less than an amountbioequivalent to 0.125 mg of naltrexone, based on the in-vitrodissolution at 1 hour of the dosage form in 900 ml of Simulated GastricFluid using a USP Type II (paddle) apparatus at 75 rpm at 37° C. and isinsufficient to produce an antagonist effect of the antagonist, but anamount of the antagonist released from said dosage form which has beentampered with and administered orally, intranasally, parenterally orsublingually is bioequivalent to 0.25 mg of naltrexone or more, based onthe in-vitro dissolution at 1 hour of the dosage form in 900 ml ofSimulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpmat 37° C., and will substantially block an effect of the agonist; theintact dosage form releasing less than 15% by weight of the opioidantagonist within 36 hours, based on the in-vitro dissolution in adissolution bath, wherein the antagonist is dispersed in a matrix ofsaid hydrophobic material.
 3. The composition of claim 1, wherein theeffect blocked by the antagonist is an analgesic effect or euphoriceffect of the agonist contained in the solid oral dosage form.
 4. Thecomposition of claim 1 which does not pose a risk of precipitation ofwithdrawal in opioid tolerant or dependent patients when the oral soliddosage form is orally administered intact.
 5. The composition of claim1, wherein the antagonist is not bioavailable when the solid oral dosageform is administered intact but is bioavailable when the solid oraldosage form is tampered with.
 6. The composition of claim 1, whereinsaid tampering is by means selected from the group consisting ofcrushing, shearing, grinding, chewing and dissolving in a solvent incombination with heating.
 7. The composition of claim 6, wherein saidtampering is by crushing.
 8. The composition of claim 1, wherein saidcomposition is formulated such that the ratio of the amount of theantagonist released from said solid oral dosage form which has beentampered with and administered orally, intranasally, parenterally orsublingually to the amount of said antagonist released from said dosageform which has been administered intact is about 4:1 or greater, basedon the in-vitro dissolution at 1 hour of said oral solid dosage form in900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatusat 75 rpm at 37° C.
 9. The composition of claim 2, wherein the effectblocked by the antagonist is an analgesic effect or euphoric effect ofthe agonist contained in the solid oral dosage form.
 10. The compositionof claim 2 which does not pose a risk of precipitation of withdrawal inopioid tolerant or dependent patients when the oral solid dosage form isorally administered intact.
 11. The composition of claim 2, wherein theantagonist is not bioavailable when the solid oral dosage form isadministered intact but is bioavailable when the solid oral dosage formis tampered with and administered orally, intranasally, parenterally orsublingually.
 12. The composition of claim 2, wherein said tampering isby means selected from the group consisting of crushing, shearing,grinding, chewing and dissolving in a solvent in combination withheating.
 13. The composition of claim 12, wherein said tampering is bycrushing.
 14. The composition of claim 2, wherein said composition isformulated such that the ratio of the amount of antagonist released fromsaid solid oral dosage form which has been tampered with andadministered orally, intranasally, parenterally or sublingually to theamount of said antagonist released from said oral solid dosage formwhich has been administered intact is about 4:1 or greater, based on thein-vitro dissolution at 1 hour of said oral solid dosage form in 900 mlof Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75rpm at 37° C.
 15. The antagonist composition of any one of claims 1, 2,3, 6, 8, 9, 11, 12, or 13, wherein the amount of the antagonist releasedat 1, 2, 4 and 12 hours from the intact dosage form, based on thein-vitro dissolution in a dissolution bath, is undetectable by HighPerformance Liquid Chromatography.
 16. The antagonist composition ofclaim 1, wherein the intact dosage form releases at least 0.025 mg ofnaltrexone or a bioequivalent dose of another antagonist at 1 hour,based on the in-vitro dissolution at 1 hour of the dosage form in 900 mlof Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75rpm at 37° C.
 17. The antagonist composition of claim 2, wherein theintact dosage form releases at least 0.025 mg of naltrexone or abioequivalent dose of another antagonist at 1 hour, based on thein-vitro dissolution at 1 hour of the dosage form in 900 ml of SimulatedGastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37° C.